Crystals of laquinimod sodium and improved process for the manufacture thereof

ABSTRACT

The subject invention provides a mixture of crystalline laquinimod sodium particles, wherein (i) 90% or more of the total amount by volume of the laquinimod sodium particles have a size of 40 microns or less or (ii) 50% or more of the total amount by volume of the laquinimod sodium particle have a size of 15 microns or less, and wherein:
         a) the mixture has a bulk density of 0.2 g/mL to 0.4 g/mL;   b) the mixture has a tapped density of 0.40 g/mL to 0.7 g/mL;   c) an amount of heavy metal in the mixture is no more than 0.002% of heavy metal relative to the amount by weight of laquinimod sodium;   d) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in the mixture is no more than 0.15% relative to the amount of laquinimod sodium as measured by HPLC;   e) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (MCQCA) in the mixture is no more than 0.15% relative to the amount of laquinimod sodium as measured by HPLC; or   f) an amount of 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (MCQME) in the mixture is no more than 0.12% relative to the amount of laquinimod sodium as measured by HPLC.

This application claims benefit of U.S. Provisional Application No.61/785,575, filed Mar. 14, 2013, the entire content of which is herebyincorporated by reference herein.

Throughout this application, various publications are referred to byfirst author and year of publication. Full citations for thesepublications are presented in a References section immediately beforethe claims. Disclosures of the publications cited in the Referencessection in their entireties are hereby incorporated by reference intothis application in order to more fully describe the state of the art asof the date of the invention described herein.

BACKGROUND OF THE INVENTION

Laquinimod is a compound which has been shown to be effective in theacute experimental autoimmune encephalomyelitis (aEAE) model (U.S. Pat.No. 6,077,851). Its chemical name isN-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide,and its Chemical Registry number is 248281-84-7.

Laquinimod is a small molecule having the following chemical structure:

The processes of synthesis of laquinimod and the preparation of itssodium salt are disclosed in U.S. Pat. No. 6,077,851. An additionalprocess of synthesis of laquinimod acid, but not laquinimod sodium,having low levels of impurities is disclosed in U.S. Pat. No. 6,875,869.U.S. Pat. No. 7,884,208 teaches a process for the preparation oflaquinimod sodium which removes the impurities present after the saltformation step, thus resulting in a crystalline mixture of higher purityas well as a crystalline mixture having large particles, and good tappedand bulk density. Pharmaceutical compositions comprising laquinimodsodium are disclosed in PCT International Application Publication No. WO2005/074899.

In the preparation or laquinimod sodium disclosed in U.S. Pat. No.6,077,851, laquinimod acid was suspended in ethanol, and 5M sodiumhydroxide solution was added. After stirring, the resulting precipitatewas filtered, washed with ethanol, and dried. The method used to makelaquinimod sodium in U.S. Pat. No. 6,077,851 is commonly referred to asa slurry-to-slurry salt formation.

In the slurry-to-slurry salt formation method of U.S. Pat. No.6,077,851, the laquinimod sodium is not dissolved in solution. Any solidimpurities, if present in the laquinimod sodium suspension, aretherefore not removed by filtration.

U.S. Pat. No. 6,875,869 discloses a process of preparing the basecompound laquinimod in high yield and low level of impurities. However,the process in U.S. Pat. No. 6,875,869 is only for synthesis of the basecompound (laquinimod acid) and not the salt. As such, theslurry-to-slurry salt formation process would still be needed to formthe sodium salt.

U.S. Pat. No. 7,884,208 teaches an improved process for preparinglaquinimod sodium resulting in crystals of higher purity as well ascrystals having improved crystalline characteristics, e.g., comprisingno more than 2 ppm of a heavy metal and having higher tapped density. Inthe process disclosed in U.S. Pat. No. 7,884,208 in Examples 13-17,laquinimod sodium is dissolved in water to form an aqueous solution; theaqueous solution is concentrated; and then a water-miscible anti-solventis added to the concentrated solution to form laquinimod sodiumcrystals. The process of U.S. Pat. No. 7,884,208 removes the impuritiesafter salt formation, thus resulting in laquinimod sodium of higherpurity than the laquinimod sodium produced directly from the “slurry toslurry” process of U.S. Pat. No. 6,077,851.

SUMMARY OF THE INVENTION

The subject invention provides a mixture of crystalline laquinimodsodium particles, wherein (i) 90% or more of the total amount by volumeof the laquinimod sodium particles have a size of 40 microns or less or(ii) 50% or more of the total amount by volume of the laquinimod sodiumparticles have a size of 15 microns or less and wherein:

-   -   a) the mixture has a bulk density of 0.2 g/mL to 0.4 g/mL;    -   b) the mixture has a tapped density of 0.40 g/mL to 0.7 g/mL;    -   c) an amount of heavy metal in the mixture is no more than        0.002% of heavy metal relative to the amount by weight of        laquinimod sodium;    -   d) an amount of        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in        the mixture is no more than 0.15% relative to the amount of        laquinimod sodium as measured by HPLC;    -   e) an amount of        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic        acid (MCQCA) in the mixture is no more than 0.15% relative to        the amount of laquinimod sodium as measured by HPLC; or    -   f) an amount of        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate        (MCQME) in the mixture is no more than 0.12% relative to the        amount of laquinimod sodium as measured by HPLC.

The subject invention provides a mixture of crystalline laquinimodsodium particles, wherein (i) 90% or more of the total amount by volumeof the laquinimod sodium particles have a size of less than 40 microns,(ii) 50% or more of the total amount by volume of the laquinimod sodiumparticles have a size of less than 15 microns, and (iii) 10% or more ofthe total amount by volume of the laquinimod sodium particles have asize of less than 5 microns and wherein:

-   -   a) the mixture has a bulk density of 0.2 g/mL to 0.4 g/mL;    -   b) the mixture has a tapped density of 0.40 g/mL to 0.7 g/mL;    -   c) an amount of heavy metal in the mixture is no more than        0.002% of heavy metal relative to the amount by weight of        laquinimod sodium;    -   d) an amount of        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in        the mixture is no more than 0.15% relative to the amount of        laquinimod sodium as measured by HPLC;    -   e) an amount of        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic        acid (MCQCA) in the mixture is no more than 0.15% relative to        the amount of laquinimod sodium as measured by HPLC; or    -   f) an amount of        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate        (MCQME) in the mixture is no more than 0.12% relative to the        amount of laquinimod sodium as measured by HPLC.

The subject invention provides a process of recrystallization oflaquinimod sodium comprising:

-   -   a) dissolving an amount of laquinimod sodium in water to form an        aqueous solution;    -   b) concentrating the aqueous solution to form a concentrated        solution comprising approximately 1.7-1.8 mL of water per gram        of laquinimod sodium;    -   c) adding acetone to the concentrated solution of step b); and    -   d) isolating recrystallized laquinimod sodium.

The subject invention provides a mixture of crystalline laquinimodsodium particles, wherein (i) 90% or more of the total amount by volumeof the laquinimod sodium particles have a size of 40 microns or less or(ii) 50% or more of the total amount by volume of the laquinimod sodiumparticles have a size of 15 microns or less, and wherein

-   -   a) an amount of aluminium in the mixture is less than 5 ppm        relative to the amount by weight of laquinimod sodium;    -   b) an amount of calcium in the mixture is less than 60 ppm        relative to the amount by weight of laquinimod sodium;    -   c) an amount of copper in the mixture is less than 1 ppm        relative to the amount by weight of laquinimod sodium;    -   d) an amount of iron in the mixture is less than 4 ppm relative        to the amount by weight of laquinimod sodium; or    -   e) an amount of zinc in the mixture is less than 7 ppm relative        to the amount by weight of laquinimod sodium.

BRIEF DESCRIPTION OF FIGURES

FIG. 1: FIG. 1 from U.S. Pat. No. 7,884,208.

FIG. 2: FIG. 2 from U.S. Pat. No. 7,884,208.

FIG. 3: HPLC Data—Example chromatogram of mixture of laquinimod sodium.

FIG. 4: HPLC Data—Pure chromatogram of Laquinimod Sodium.

FIG. 5: Microscopic photograph of typical batch of crude LaquinimodSodium at a first magnification level.

FIG. 6: Microscopic photograph of typical batch of crude LaquinimodSodium at a second magnification level.

FIG. 7: Microscopic photograph of Batch C at a first magnificationlevel.

FIG. 8: Microscopic photograph of Batch C at a second magnificationlevel.

DETAILED DESCRIPTION OF THE INVENTION

The subject invention provides a mixture of crystalline laquinimodsodium particles, wherein (i) 90% or more of the total amount by volumeof the laquinimod sodium particles have a size of 40 microns or less or(ii) 50% or more of the total amount by volume of the laquinimod sodiumparticles have a size of 15 microns or less, and wherein:

-   -   a) the mixture has a bulk density of 0.2 g/mL to 0.4 g/mL;    -   b) the mixture has a tapped density of 0.40 g/mL to 0.7 g/mL;    -   c) an amount of heavy metal in the mixture is no more than        0.002% of heavy metal relative to the amount by weight of        laquinimod sodium;    -   d) an amount of        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in        the mixture is no more than 0.15% relative to the amount of        laquinimod sodium as measured by HPLC;    -   e) an amount of        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic        acid (MCQCA) in the mixture is no more than 0.15% relative to        the amount of laquinimod sodium as measured by HPLC; or    -   f) an amount of        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate        (MCQME) in the mixture is no more than 0.12% relative to the        amount of laquinimod sodium as measured by HPLC.

In an embodiment of the mixture, (i) 90% or more of the total amount byvolume of the laquinimod sodium particles have a size of less than 40microns or (ii) 50% or more of the total amount by volume of thelaquinimod sodium particles have a size of less than 15 microns.

In an embodiment of the mixture, 10% or more of the total amount byvolume of the laquinimod sodium particles have a size of 5 microns orless and wherein:

-   -   a) the mixture has a tapped density of 0.40 g/mL to 0.7 g/mL; or    -   b) an amount of        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in        the mixture is no more than 0.15% relative to the amount of        laquinimod sodium as measured by HPLC.

The subject invention provides a mixture of crystalline laquinimodsodium particles, wherein (i) 90% or more of the total amount by volumeof the laquinimod sodium particles have a size of less than 40 microns,(ii) 50% or more of the total amount by volume of the laquinimod sodiumparticles have a size of less than 15 microns, and (iii) 10% or more ofthe total amount by volume of the laquinimod sodium particles have asize of less than 5 microns and wherein:

-   -   a) the mixture has a bulk density of 0.2 g/mL to 0.4 g/mL;    -   b) the mixture has a tapped density of 0.40 g/mL to 0.7 g/mL;    -   c) an amount of heavy metal in the mixture is no more than        0.002% of heavy metal relative to the amount by weight of        laquinimod sodium;    -   d) an amount of        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in        the mixture is no more than 0.15% relative to the amount of        laquinimod sodium as measured by HPLC;    -   e) an amount of        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic        acid (MCQCA) in the mixture is no more than 0.15% relative to        the amount of laquinimod sodium as measured by HPLC; or    -   f) an amount of        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate        (MCQME) in the mixture is no more than 0.12% relative to the        amount of laquinimod sodium as measured by HPLC.

In an embodiment of the mixture, the mixture is prepared in a singlebatch comprising 2.5 kg or more of laquinimod sodium.

In an embodiment of the mixture, the laquinimod sodium particles aredetermined based on an unmilled sample of the mixture.

In an embodiment of the mixture, the size and amount by volume oflaquinimod sodium particles are determined based on a milled sample ofthe mixture.

In an embodiment of the mixture, the mixture has a bulk density of 0.2g/mL to 0.4 g/mL.

In an embodiment of the mixture, the mixture has a tapped density of0.40 g/mL to 0.7 g/mL.

In an embodiment of the mixture, an amount of aluminium in the mixtureis less than 5 ppm relative to the amount by weight of laquinimodsodium.

In an embodiment of the mixture, an amount of aluminium in the mixtureis less than 2 ppm relative to the amount by weight of laquinimodsodium.

In an embodiment of the mixture, an amount of calcium in the mixture isless than 60 ppm relative to the amount by weight of laquinimod sodium.

In an embodiment of the mixture, an amount of calcium in the mixture isless than 25 ppm relative to the amount by weight of laquinimod sodium.

In an embodiment of the mixture, an amount of copper in the mixture isless than 1 ppm relative to the amount by weight of laquinimod sodium.

In an embodiment of the mixture, an amount of copper in the mixture isless than 0.6 ppm relative to the amount by weight of laquinimod sodium.

In an embodiment of the mixture, an amount of iron in the mixture isless then 4 ppm relative to the amount by weight of laquinimod sodium.

In an embodiment of the mixture, an amount of iron in the mixture isless than 3.6 ppm relative to the amount by weight of laquinimod sodium.

In an embodiment of the mixture, an amount of zinc in the mixture isless than 7 ppm relative to the amount by weight of laquinimod sodium.

In an embodiment of the mixture, an amount of zinc in the mixture isless than 4 ppm relative to the amount by weight of laquinimod sodium.

In an embodiment of the mixture, an amount of heavy metal is the mixtureis no more than 20 ppm relative to the amount by weight of laquinimodsodium.

In an embodiment of the mixture, an amount of heavy metal in the mixtureis no more than 2 ppm relative to the amount by weight of laquinimodsodium.

In an embodiment of the mixture, a total amount of polar impurities inthe mixture is no more than 1.00% relative to the amount of laquinimodsodium as measured by HPLC.

In an embodiment of the mixture, an amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in themixture is no more than 0.15% relative to the amount of laquinimodsodium as measured by HPLC.

In an embodiment of the mixture, an amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(MCQCA) in the mixture is no more than 0.15% relative to the amount oflaquinimod sodium as measured by HPLC.

In an embodiment of the mixture, an amount of methyl5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate(MCQME) in the mixture is no more than 0.12% relative to the amount oflaquinimod sodium as measured by HPLC.

In an embodiment of the mixture, an amount of ethyl5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate(MCQEE) in the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC.

In an embodiment of the mixture, a total amount of non-polar impuritiesin the mixture is no more than 0.50% relative to the amount oflaquinimod sodium as measured by HPLC.

In an embodiment of the mixture, an amount of N-ethyl aniline in themixture is no more than 0.10% relative to the amount of laquinimodsodium as measured by HPLC.

In an embodiment of the mixture, an amount ofN-ethyl-4,5-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydroquinoline-3-carboxamide(5-HLAQ) in the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC.

In an embodiment of the mixture, an amount of5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide(DELAQ) in the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC.

In an embodiment of the mixture, an amount of laquinimod acid in themixture is no more than 1.00% relative to the amount of laquinimodsodium as measured by HPLC.

In an embodiment of the mixture, an amount of dimethyl malonate in themixture is no more than 0.10% relative to the amount of laquinimodsodium as measured by HPLC.

In an embodiment of the mixture, an amount of diethyl malonate in themixture is no more than 0.10% relative to the amount of laquinimodsodium as measured by HPLC.

In an embodiment of the mixture, an amount of dimethyl sulfate is themixture is no more than 1 ppm relative to the amount by weight oflaquinimod sodium.

In an embodiment of the mixture, an amount of water in the mixture is nomore than 1.5% by weight relative to the amount of laquinimod sodium asmeasured by K.F. coulometric titration.

In an embodiment of the mixture, an amount of sodium from 5.8% to 6.4%relative to the amount by weight of laquinimod sodium.

In an embodiment of the mixture, an amount of ethanol in the mixture isno more than 5000 ppm relative to the amount by weight of laquinimodsodium.

In an embodiment of the mixture, an amount of n-heptane in the mixtureis no more than 5000 ppm relative to the amount by weight of laquinimodsodium.

In an embodiment of the mixture, an amount of n-heptane in the mixtureis no more than 2000 ppm n-octane relative to the amount by weight oflaquinimod sodium.

In an embodiment of the mixture, an amount of methanol in the mixture isno more than 3000 ppm relative to the amount by weight of laquinimodsodium.

In an embodiment of the mixture, an amount of acetone in the mixture isno more than 5000 ppm relative to the amount by weight of laquinimodsodium.

In an embodiment of the mixture, an amount of dioxane in the mixture isno more then 380 ppm relative to the amount by weight of laquinimodsodium.

In an embodiment of the mixture, an amount of dimethyl formamide in themixture is no more than 880 ppm relative to the amount by weight oflaquinimod sodium.

The subject invention provides a pharmaceutical composition comprisingthe mixture of of the subject invention and a pharmaceuticallyacceptable carrier.

In an embodiment of the pharmaceutical composition, a total amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) and5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(MCQCA) in the pharmaceutical composition is no more than 0.50% relativeto the amount of laquinimod sodium as measured by HPLC.

In an embodiment of the pharmaceutical composition, a total amount ofpolar impurities in the pharmaceutical composition is no more than 2.00%relative to the amount of laquinimod sodium as measured by HPLC.

In an embodiment of the pharmaceutical composition, an amount of N-ethylaniline in the pharmaceutical composition is no more than 0.50% relativeto the amount of laquinimod sodium as measured by HPLC.

In an embodiment of the pharmaceutical composition, an amount of5-chloro-N-ethyl-3-hydroxy-1-methyl-5-2,4-dioxo-N-phenyl-1,2,3,4-tetrahydroquinoline-3-carboxamide(3-HLAQ) in the pharmaceutical composition is no more than 0.50%relative to the amount of laquinimod sodium as measured by HPLC.

In an embodiment of the pharmaceutical composition, a total amount ofnon-polar impurities in the pharmaceutical composition is no more than1.00% relative to the amount of laquinimod sodium as measured by HPLC.

In an embodiment of the pharmaceutical composition, an amount ofN-ethyl-4-hydroxy-1-methyl-5-(methyl(2,3,4,5,6-pentahydroxyhexyl)amino)-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide(MEG-LAQ) in the pharmaceutical composition is no more than 1.00%relative to the amount of laquinimod sodium as measured by HPLC.

In an embodiment of the pharmaceutical composition, an amount of waterin the pharmaceutical composition is no more than 1.50% relative to theamount of laquinimod sodium as measured by K.F. coulometric titration.

In an embodiment of the pharmaceutical composition, an amount of waterin the pharmaceutical composition is no more than 0.80% relative to theamount of laquinimod sodium as measured by K.F. coulometric titration.

In an embodiment of the pharmaceutical composition, an amount of sodiumfrom 5.8% to 6.4% relative to the amount by weight of laquinimod sodium.

In an embodiment of the pharmaceutical composition, an amount of ethanolin the pharmaceutical composition is no more than 5000 ppm relative tothe amount by weight of laquinimod sodium.

In an embodiment of the pharmaceutical composition, an amount ofn-heptane in the pharmaceutical composition is no more than 5000 ppmrelative to the amount by weight of laquinimod sodium;

In an embodiment of the pharmaceutical composition, an amount ofn-octane in the pharmaceutical composition is no more than 2000 ppmrelative to the amount by weight of laquinimod sodium.

In an embodiment of the pharmaceutical composition, an amount ofmethanol in the pharmaceutical composition is no more than 380 ppmrelative to the amount by weight of laquinimod sodium.

In an embodiment of the pharmaceutical composition, an amount of acetonein the pharmaceutical composition is no more than 880 ppm relative tothe amount by weight of laquinimod sodium.

In an embodiment the pharmaceutical composition, an amount of dioxane inthe pharmaceutical composition is no more than 380 ppm relative to theamount by weight of laquinimod sodium.

In an embodiment of the pharmaceutical composition, an amount ofdimethyl formamide in the pharmaceutical composition is no more than 880ppm relative to the amount by weight of laquinimod sodium.

The subject invention provides a method of treating a subject afflictedwith a form of multiple sclerosis, lupus nephritis, lupus arthritis,rheumatoid arthritis, a BDNF-related disorder, Crohn's disease, aGABA-related disorder, a cannabinoid receptor type 1 (CB1) mediateddisorder, or an ocular inflammatory disorder comprising administering tothe subject the mixture of the subject invention or the pharmaceuticalcomposition of the subject invention so as to thereby treat the subject.

The subject invention provides a method for alleviating a symptom ofmultiple sclerosis, lupus nephritis, lupus arthritis, rheumatoidarthritis, a BDNF-related disorder, Crohn's disease, a GABA-relateddisorder, a cannabinoid receptor type 1 (CB1) mediated disorder, or anocular inflammatory disorder in a subject afflicted with a form ofmultiple sclerosis comprising administering to the subject the mixtureof any one of the subject invention or the pharmaceutical composition ofthe subject invention thereby alleviating the symptom of multiplesclerosis in the subject.

In one embodiment, the mixture or the pharmaceutical composition for usein the treatment of, or alleviation of symptoms of, a form of multiplesclerosis, lupus nephritis, lupus arthritis, rheumatoid arthritis, aBDNF-relatad disorder, Crohn's disease, a GABA-related disorder, acannabinoid receptor type 1 (CB1) mediated disorder, or an ocularinflammatory disorder.

The subject invention provides a use of the mixture or thepharmaceutical composition for the manufacture of a medicament fortreating, or alleviating a symptom of, a form of multiple sclerosis, aGABA-related disorder, a cannabinoid receptor type 1 (CB1) mediateddisorder, lupus nephritis, lupus arthritis, rheumatoid arthritis, aBDNF-related disorder, Crohn's disease or an ocular inflammatorydisorder.

The subject invention provides a process of recrystallization oflaquinimod sodium comprising:

-   -   a) dissolving an amount of laquinimod sodium in water to form an        aqueous solution;    -   b) concentrating the aqueous solution to form a concentrated        solution comprising approximately 1.7-1.8 mL of water per gram        of laquinimod sodium;    -   c) adding acetone to the concentrated solution of step b); and    -   d) isolating recrystallized laquinimod sodium.

In an embodiment of the process, the amount of laquinimod sodium in stepa) is 2.5 kg or greater.

In an embodiment of the process, step a) is performed with 10-12 mL ofmater per gram of laquinimod sodium.

In an embodiment of the process, step a) is performed with approximately11 mL of water per gram of laquinimod sodium.

In an embodiment of the process, step a) is performed by heating theaqueous solution to a temperature of 58-75° C.

In an embodiment of the process, step a) is performed by heating theaqueous solution to a temperature of 60-73° C.

In an embodiment of the process, crystallization occurs after step a)and before step c).

In an embodiment of the process, crystallization is induced by rapidstirring during or after the concentrating step b).

In an embodiment of the process, crystallization is induced by additionof a seed crystal during or after the concentrating step b).

In an embodiment of the process, crystallization occurs without additionof a seed crystal.

In an embodiment of the process, step b) is performed under conditionsappropriate to induce crystallization at the concentration of 1.7-1.8 mLof water per gram of laquinimod sodium.

In an embodiment of the process, step b) is performed at 28-45° C.

In an embodiment of the process, step b) is performed at 30-40° C.

In an embodiment of the process, step c) is performed with theconcentrated solution at 40-55° C.

In an embodiment of the process, step c) is performed with theconcentrated solution at 45-50° C.

In an embodiment of the process, step c) is performed with 6-12 mL ofacetone per gram of laquinimod sodium.

In an embodiment of the process, step c) is performed with approximately10 mL of acetone per gram or laquinimod sodium.

In an embodiment of the process, step c) is performed over a period of1-4 hours.

In an embodiment of the process, step c) is performed over a period of1.2-2.5 hours.

In an embodiment of the process, step c) is followed by cooling thesolution to a temperature no less than −14° C. and no more than 6° C.

In an embodiment of the process, step c) is followed by cooling thesolution to a temperature no less then −4° C. and no more than 4° C.

In an embodiment of the process, the solution is cooled over a period of3-5 hours.

In an embodiment of the process, the solution is cooled over a period of3.5-4.5 hours.

In an embodiment of the process, step d) further comprises washing therecrystallized laquinimod sodium with 1-4 mL of acetone per gram ofcrude laquinimod sodium used in step a).

In an embodiment of the process, step d) further comprises washing therecrystallized laquinimod sodium with approximately 3 mL of acetone pergram of crude laquinimod sodium used in step a).

In an embodiment of the process, step d) further comprises drying therecrystallized laquinimod sodium for no less than one hour at 30-40° C.under a vacuum of no more than 50 mmHg.

In an embodiment of the process, the isolated recrystallized laquinimodsodium; in step d) is a mixture of crystalline laquinimod sodiumparticles having a particle size distribution such that (i) 90% or moreof the total amount by volume of the laquinimod sodium particles have asize of 40 microns or less, (ii) 50% or more of the total amount byvolume of the laquinimod sodium particles have a size of 15 microns orless, and (iii) 10% or more of the total amount by volume of thelaquinimod sodium particles have a size of less than 5 microns or less.

The subject invention provides a mixture of crystalline laquinimodsodium particles prepared by the process of the subject invention.

In an embodiment of the mixture of crystalline laquinimod sodiumparticles prepared by the process of the subject invention, (i) 90% ormore of the total amount by volume of the laquinimod sodium particleshave a size of 40 microns or less, (ii) 50% or more of the total amountby volume of the laquinimod sodium particles have a size of 15 micronsor less, and (iii) 10% or more of the total amount by volume of thelaquinimod sodium particles have a size of 5 microns or less.

In an embodiment of the mixture,

-   -   a) the mixture has a bulk density of 0.2 g/mL to 0.4 g/mL;    -   b) the mixture has a tapped density of 0.40 g/mL to 0.7 g/mL;    -   c) an amount of aluminium in the mixture is less than 5 ppm        relative to the amount by weight of laquinimod sodium;    -   d) an amount of calcium in the mixture is less than 60 ppm        relative to the amount by weight of laquinimod sodium;    -   e) an amount of copper in the mixture is less than 1 ppm        relative to the amount by weight of laquinimod sodium;    -   f) an amount of iron in the mixture is less than 4 ppm relative        to the amount by weight of laquinimod sodium;    -   g) an amount of zinc in the mixture is less than 7 ppm relative        to the amount by weight of laquinimod sodium;    -   h) an amount of heavy metal in the mixture is no more than        0.002% relative to the amount by weight of laquinimod sodium;    -   i) a total amount of polar impurities in the mixture is no more        than 1.00% relative to the amount of laquinimod sodium as        measured by HPLC;    -   j) an amount of        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in        the mixture is no more than 0.15% relative to the amount of        laquinimod sodium as measured by HPLC;    -   k) an amount of        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic        acid (MCQCA) in the mixture is no more than 0.15% relative to        the amount of laquinimod sodium as measured by HPLC;    -   l) an amount of methyl        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate        (MCQME) the mixture is no more than 0.12% relative to the amount        of laquinimod sodium as measured by HPLC;    -   m) an amount of ethyl        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate        (MCQEE) in the mixture is no more than 0.10% relative to the        amount of laquinimod sodium as measured by HPLC;    -   n) a total amount of non-polar impurities in the mixture is no        more than 0.50% relative to the amount of laquinimod sodium as        measured by HPLC;    -   o) an amount of N-ethyl aniline in the mixture is no more than        0.10% relative to the amount of laquinimod sodium as measured by        HPLC;    -   p) an amount of laquinimod acid in the mixture is no more than        1.00% relative to the amount of laquinimod sodium as measured by        HPLC;    -   q) an amount of dimethyl malonate in the mixture is no more than        0.10% relative to the amount of laquinimod sodium as measured by        HPLC;    -   r) an amount of diethyl malonate in the mixture is no more than        0.10% relative to the amount of laquinimod sodium as measured by        HPLC;    -   s) an amount of dimethyl sulfate in the mixture is no more than        1 ppm relative to the amount by weight of laquinimod sodium;    -   t) an amount of water in the mixture is no more than 1.5% by        weight relative to the amount of laquinimod sodium as measured        by K.F. coulometric titration;    -   u) the mixture comprises an amount of sodium from 5.8% to 6.4%        relative to the amount by weight of laquinimod sodium;    -   v) an amount of ethanol in the mixture is no more than 5000 ppm        relative to the amount by weight of laquinimod sodium;    -   w) an amount of n-heptane in the mixture is no more than 5000        ppm relative to the amount by weight of laquinimod sodium;    -   x) an amount of n-heptane in the mixture is no more than 2000        ppm n-octane relative to the amount by weight of laquinimod        sodium;    -   y) an amount of methanol in the mixture is no more than 3000 ppm        relative to the amount by weight of laquinimod sodium;    -   z) an amount of acetone in the mixture is no more than 5000 ppm        relative to the amount by weight of laquinimod sodium;    -   aa) an amount of dioxane in the mixture is no more than 380 ppm        relative to the amount by weight of laquinimod sodium; or    -   bb) an amount of dimethyl formamide in the mixture is no more        than 880 ppm relative to the amount by weight of laquinimod        sodium.

In an embodiment of the mixture,

-   -   a) the mixture has a bulk density of 0.2 g/mL to 0.4 g/mL;    -   b) the mixture has a tapped density of 0.40 g/mL to 0.7 g/mL;    -   c) an amount of aluminium in the mixture is less than 5 ppm        relative to the amount by weight of laquinimod sodium;    -   d) an amount of calcium in the mixture is less than 60 ppm        relative to the amount by weight of laquinimod sodium;    -   e) an amount of cooper in the mixture is less than 1 ppm        relative to the amount by weight of laquinimod sodium;    -   f) an amount of iron in the mixture is less than 4 ppm relative        to the amount by weight of laquinimod sodium;    -   g) an amount of zinc in the mixture is less than 7 ppm relative        to the amount by weight of laquinimod sodium;    -   h) an amount of heavy metal in the mixture is no more than        0.002% relative to the amount by weight of laquinimod sodium;    -   i) a total amount of polar impurities in the mixture is no more        than 1.00% relative to the amount of laquinimod sodium as        measured by HPLC;    -   j) an amount of        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in        the mixture is no more than 0.15% relative to the amount of        laquinimod sodium as measured by HPLC;    -   k) an amount of        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate        acid (MCQCA) in the mixture is no more than 0.15% relative to        the amount of laquinimod sodium as measured by HPLC;    -   l) an amount of methyl        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate        (MCQME) in the mixture is no more than 0.12% relative to the        amount of laquinimod sodium as measured by HPLC;    -   m) an amount of ethyl        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate        (MCQEE) in the mixture is no more than 0.10% relative to the        amount of laquinimod sodium as measured by HPLC;    -   n) a total amount of non-polar impurities is the mixture is no        more than 0.50% relative to the amount of laquinimod sodium as        measured by HPLC;    -   o) an amount of N-ethyl aniline in the mixture is no more than        0.10% relative to the amount of laquinimod sodium as measured by        HPLC;    -   p) an amount of laquinimod acid in the mixture is no more than        1.00% relative to the amount of laquinimod sodium as measured by        HPLC;    -   q) an amount of dimethyl malonate in the mixture is no more than        0.10% relative to the amount of laquinimod sodium as measured by        HPLC;    -   r) an amount of diethyl malonate in the mixture is no more than        0.10% relative to the amount of laquinimod sodium as measured by        HPLC;    -   s) an amount of dimethyl sulfate in the mixture is no more than        1 ppm relative to the amount by weight of laquinimod sodium;    -   t) an amount of water in the mixture is no more than 1.5% by        weight relative to the amount of laquinimod sodium as measured        by K.F. coulometric titration;    -   u) the mixture comprises an amount of sodium from 5.8% to 6.4%        relative to the amount by weight of laquinimod sodium;    -   v) an amount of ethanol in the mixture is no more than 5000 ppm        relative to the amount by weight of laquinimod sodium;    -   w) an amount of n-heptane in the mixture is no more than 5000        ppm relative to the amount by weight of laquinimod sodium;    -   x) an amount of n-heptane in the mixture is no more than 2000        ppm n-octane relative to the amount by weight of laquinimod        sodium;    -   y) an amount of methanol in the mixture is no more than 3000 ppm        relative to the amount by weight of laquinimod sodium;    -   z) an amount of acetone in the mixture is no more than 5000 ppm        relative to the amount by weight of laquinimod sodium;    -   aa) an amount of dioxane in the mixture is no more than 380 ppm        relative to the amount by weight of laquinimod sodium; and    -   bb) an amount of dimethyl formamide in the mixture is no more        than 880 ppm relative to the amount by weight of laquinimod        sodium.

The subject invention provides a pharmaceutical composition comprisingthe mixture of crystalline laquinimod sodium particles prepared by theprocess of the subject invention, and a pharmaceutically acceptablecarrier.

In an embodiment of the pharmaceutical composition,

-   -   a) a total amount of        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) and        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic        acid (MCQCA) in the pharmaceutical composition is no more than        0.50% relative to the amount of laquinimod sodium as measured by        HPLC;    -   b) a total amount of polar impurities in the pharmaceutical        composition is no more then 2.00% relative to the amount of        laquinimod sodium as measured by HPLC;    -   c) an amount of N-ethyl aniline in the pharmaceutical        composition is no more than 0.50% relative to the amount of        laquinimod sodium as measured by HPLC;    -   d) a total amount of non-polar impurities in the pharmaceutical        composition is no more than 1.00% relative to the amount of        laquinimod sodium as measured by HPLC;    -   e) an amount of water in the pharmaceutical composition is no        more then 0.80% relative to the amount of laquinimod sodium as        measured by K.F. coulometric titration;    -   f) the pharmaceutical composition comprises an amount of sodium        from 5.8% to 6.4% relative to the amount by weight of laquinimod        sodium;    -   g) an amount of ethanol in the pharmaceutical composition is no        more than 5000 ppm relative to the amount by weight of        laquinimod sodium;    -   h) an amount of n-heptane in the pharmaceutical composition is        no more than 5000 ppm relative to the amount by weight of        laquinimod sodium;    -   i) an amount of n-octane in the pharmaceutical composition is no        more than 2000 ppm relative to the amount by weight of        laquinimod sodium;    -   j) an amount of methanol in the pharmaceutical composition is no        more than 380 ppm relative to the amount by weight of laquinimod        sodium;    -   k) an amount of acetone in the pharmaceutical composition is no        more than 880 ppm relative to the amount by weight of laquinimod        sodium;    -   l) an amount of dioxane in the pharmaceutical composition is no        more than 380 ppm relative to the amount by weight of laquinimod        sodium; or    -   m) an amount of dimethyl formamide in the pharmaceutical        composition is no more than 880 ppm relative to the amount by        weight of laquinimod sodium.

In an embodiment of the pharmaceutical composition,

-   -   a) a total amount of        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) and        5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic        acid (MCQCA) in the pharmaceutical composition is no more than        0.50% relative to the amount of laquinimod sodium as measured by        HPLC;    -   b) a total amount of polar impurities in the pharmaceutical        composition is no more than 2.00% relative to the amount of        laquinimod sodium as measured by HPLC;    -   c) an amount of N-ethyl aniline in the pharmaceutical        composition is no more than 0.50% relative to the amount of        laquinimod sodium as measured by HPLC;    -   d) a total amount of non-polar impurities in the pharmaceutical        composition is no more than 1.00% relative to the amount of        laquinimod sodium as measured by HPLC;    -   e) as an amount of water in the pharmaceutical composition is no        more than 0.80% relative to the amount of laquinimod sodium as        measured by K.F. coulometric titration;    -   f) the pharmaceutical composition comprises an amount of sodium        from 5.8% to 6.4% relative to the amount by weight of laquinimod        sodium;    -   g) an amount of ethanol in the pharmaceutical composition is no        more than 5000 ppm relative to the amount by weight of        laquinimod sodium;    -   h) an amount of n-heptane in the pharmaceutical composition is        no more than 5000 ppm relative to the amount by weight of        laquinimod sodium;    -   i) an amount of n-octane in the pharmaceutical composition is no        more than 2000 ppm relative to the amount by weight of        laquinimod sodium;    -   j) an amount of methanol in the pharmaceutical composition is no        more than 380 ppm relative to the amount by weight of laquinimod        sodium;    -   k) an amount of acetone in the pharmaceutical composition is no        more than 880 ppm relative to the amount by weight of laquinimod        sodium;    -   l) an amount of dioxane in the pharmaceutical composition is no        more than 380 ppm relative to the amount by weight of laquinimod        sodium; and    -   m) an amount of dimethyl formamide in the pharmaceutical        composition is no more than 880 ppm relative to the amount by        weight of laquinimod sodium.

The subject invention provides a mixture of crystalline laquinimodsodium particles, wherein (i) 90% or more of the total amount by volumeof the laquinimod sodium particles have a size of 40 microns or less or(ii) 50% or more of the total amount by volume of the laquinimod sodiumparticles have a size of 15 microns or less, and wherein

-   -   a) an amount of aluminium in the mixture is less than 5 ppm        relative to the amount by weight of laquinimod sodium;    -   b) an amount of calcium in the mixture is less than 60 ppm        relative to the amount by weight of laquinimod sodium;    -   c) an amount of copper in the mixture is less than 1 ppm        relative to the amount by weight of laquinimod sodium;    -   d) an amount of iron in the mixture is less than 4 ppm relative        to the amount by weight of laquinimod sodium; or    -   e) an amount of zinc in the mixture is less than 7 ppm relative        to the amount by weight of laquinimod sodium.

The subject invention provides a pharmaceutical composition comprisingthe mixture of the subject invention and a pharmaceutically acceptablecarrier.

In an embodiment of the mixture, 90% or more of the total amount byvolume of the laquinimod sodium particles have a size of 1 micron orgreater, 2 microns or greater, 3 microns or greater or 4 microns orgreater.

In an embodiment of the mixture, 90% of the total amount by volume ofthe laquinimod sodium particles have a size of greater then 1 micron,greater than 2 microns, greater then 3 microns, greater than 4 micronsor greater than 5 microns.

In a further embodiment of the mixture, the mixture has a tapped densityof 0.4 g/mL to 0.7 g/mL, 0.44 g/mL to 0.7 g/mL, 0.45 g/mL to 0.7 g/mL,0.46 g/mL to 0.7 g/mL or 0.5 g/mL to 0.7 g/mL.

In a further embodiment of the mixture, the mixture has a bulk densityof 0.2 g/mL to 0.4 g/mL, 0.2 g/mL to 0.33 g/mL, 0.2 g/mL to 0.31 g/mL.

In a further embodiment of the pharmaceutical composition, thepharmaceutical composition comprises mannitol.

In a further embodiment of the pharmaceutical composition, thepharmaceutical composition comprises meglumine.

In a further embodiment of the pharmaceutical composition, thepharmaceutical composition comprises sodium stearyl fumarate.

In a further embodiment of the pharmaceutical composition, not less than70% of the labeled amount of laquinimod is dissolved in 30 minutes.

In a further embodiment of the pharmaceutical composition, capsules ofthe pharmaceutical composition contain 90-110% of the labeled amount oflaquinimod.

In a further embodiment of the pharmaceutical composition, capsules ofthe pharmaceutical composition contain 95-105% of the labeled amount oflaquinimod.

In a further embodiment of the pharmaceutical composition, capsules ofthe pharmaceutical composition contain 98.0-102.0% of the labeled amountof laquinimod.

In a further embodiment of the pharmaceutical composition, thepharmaceutical composition has content uniformity conforming to the U.S.Pharmacopeia.

In a further embodiment of the pharmaceutical composition, thepharmaceutical composition has content uniformity conforming to EuropeanPharmacopeia.

Each embodiment disclosed herein is contemplated as being applicable toeach of the other disclosed embodiments. Thus, all combinations of thevarious elements described herein are within the scope of the invention.For example, any embodiment for an element of a mixture a contemplatedas being applicable to a pharmaceutical composition. As another example,an embodiment to a tapped density of 0.46 g/mL to 0.7 g/mL iscontemplated as being applicable to a mixture having an amount ofaluminium in the mixture less than 5 ppm relative to the amount byweight of laquinimod sodium.

Comparison to the Prior Art

Applicants have unexpectedly achieved a mixture of crystallinelaquinimod sodium that is improved over the laquinimod sodium of theprior art.

The prior art U.S. Pat. No. 7,884,208 teaches a process ofrecrystallization of laquinimod sodium which produces and a mixture ofcrystalline laquinimod sodium having larger crystals, lowered impuritylevels and some improved crystalline characteristics.

Specifically, U.S. Pat. No. 7,884,208 achieves a mixture of crystallinelaquinimod sodium having all four of the following aspects: (i) amixture wherein 10% or more of the total amount by volume of thelaquinimod sodium particles has a size of greater than 40 microns andwherein 50% or more of the total amount by volume of the laquinimodsodium particles has a size of greater than 15 microns, (ii) highdensity (tapped and bulk), (iii) low heavy metal content, and (iv) lowpolar impurity content.

However, the recrystallization process of U.S. Pat. No. 7,884,208.(Examples 13-17, Tables 1-4) does not produce a mixture ofrecrystallized laquinimod sodium particles wherein 90% or more of thetotal amount by volume of the laquinimod sodium have a size of 40microns or less, or 50% or more of the total amount by volume of thelaquinimod sodium has a size of 15 microns or less.

Likewise, the recrystallization process of U.S. Pat. No. 7,884,208 doesnot produce a mixture of recrystallized laquinimod sodium particleswherein 90% or more of the total amount by volume of the laquinimodsodium have a size of less than 40 microns, wherein 50% or more of thetotal amount by volume of the laquinimod sodium has a size of less than15 microns, and wherein 10% or more of the total amount by volume of thelaquinimod sodium has a size of less than 5 microns.

Example 14 of U.S. Pat. No. 7,884,208 produced a mixture ofrecrystallized laquinimod sodium particles wherein 10% or more of thetotal amount by volume of the laquinimod sodium have a size of less than5 microns. However, this Example also shows reduced quality ofcrystalline characteristics, specifically Tapped Density. The mixtureproduced by Example 14 has an acceptable D(0.1) value but an undesiredTapped Density.

Conversely, Example 13 of U.S. Pat. No. 7,884,208 produced a mixturehaving high Tapped Density, but did not produce crystals wherein 90% ormore of the total amount by volume of the laquinimod sodium particleshave a size of 40 microns or less or 50% or more of the total amount byvolume of the laquinimod sodium particles have a size of 15 microns orless.

Importantly, U.S. Pat. No. 7,884,208 is unable to achieve the advantagesof recrystallization, i.e., better density and impurity profiles, whilealso producing laquinimod sodium crystals wherein 90% or more of thetotal amount by volume of the laquinimod sodium particles have a size of40 microns or less, or 50% or more of the total amount by volume of thelaquinimod sodium particles have a size of 15 microns or less.

U.S. Pat. No. 7,884,208, by way of Example 1 (batches A, B and C) andTables 1-3, also teaches that the process disclosed in U.S. Pat. No.6,077,851 results in a mixture of crystalline laquinimod sodium havingall four of the following aspects: (i) 90% or more of the total amountby volume of the laquinimod sodium particles have a size of 40 micronsor less, or 50% or more of the total amount by volume of the laquinimodsodium particles have a size of 15 microns or less, (ii) poor density(tapped and bulk), (iii) high heavy metal content, and (iv) high polarimpurity content. Importantly, although U.S. Pat. No. 6,077,851 achievesa mixture wherein 90% or more of the total amount by volume of thelaquinimod sodium particles have a size of 40 microns or less or, 50% ormore of the total amount by volume of the laquinimod sodium particleshave a size of 15 microns or less, but it does not achieve crystalshaving acceptable density or low levels of impurities.

The prior art contains no teaching of a process for preparing laquinimodsodium wherein 90% or more of the total amount by volume of thelaquinimod sodium particles have a size of 40 microns or less, or 50% ormore of the total amount by volume of the laquinimod sodium particleshave a size of 15 microns or less, and having desirable density andpurity profiles.

The present invention achieves a mixture of recrystallized laquinimodsodium crystals wherein 90% or more of the total amount by volume of thelaquinimod sodium particles have a size of 40 microns or less or (ii)50% or more of the total amount by volume of the laquinimod sodiumparticles have a size of 15 microns or less, and having desirabledensity and purity profiles, specifically, (i) high density (tapped orbulk), (ii) low heavy metal content, or (iii) low polar impuritycontact.

The laquinimod sodium of the subject invention is achieved by animproved recrystallization process.

Improved Recrystallization Process

The laquinimod sodium manufactured by the recrystallization processes ofthe present invention has improved purity and density profiles over thelaquinimod sodium disclosed in U.S. Pat. No. 6,077,851 and improvedcrystalline characteristics, especially smaller particles, over U.S.Pat. No. 7,884,208.

The modified recrystallization process of the present inventionunexpectedly results in different recrystallization conditions thanachieved by the process disclosed in U.S. Pat. No. 7,884,208 and,thusly, results in different products. Specifically, concentrating theaqueous solution to 1.7-1.8 unexpectedly results in crystallinelaquinimod sodium particles having reduced levels of impurities,improved crystalline characteristics, and wherein 90% or more of thetotal amount by volume of the laquinimod sodium particles have a size of40 microns or less, 50% or more of the total amount by volume of thelaquinimod sodium particles have a size of 15 microns or less, and 10%or more of the total amount by volume of the laquinimod sodium particleshave a size of 5 microns or less.

Without being limited to any one particular theory, an important factoraffecting crystallization is initial concentration of crystallizingsolution. Careful control of concentration of the solution canfacilitate initiation of spontaneous crystallization prior to the end ofthe concentration step. The process of the present invention caninitiate spontaneous crystallization prior to addition of acetone.

Concentrating the aqueous solution to form a concentrated solutioncomprising approximately 1.7-1.8 mL of water per gram of laquinimodsodium is an important aspect of the present invention.

Improved Mixture of Crystalline Laquinimod Sodium

U.S. Pat. No. 7,884,208 teaches advantages associated with largeparticles. Specifically, U.S. Pat. No. 7,884,208 teaches that largerparticles of laquinimod sodium are more “processable” when makingpharmaceutical compositions and that smaller particles are oftenassociated with dust-like properties which may interfere withprocessing, and sometimes associated with flowability problems which mayinterfere with manufacturing. Further, U.S. Pat. No. 7,884,208 teachesthat chemical stability has been shown to be decreased by the increasein surface area that results from smaller particle size. (Felmeister, A.Chpt 88, Remington's Pharmaceutical Sciences, 15^(th) Edition, MackPublishing Company, Easton, Pa. (1975)).

However, the subject invention has unexpectedly achieved an improvedmixture of laquinimod sodium wherein (i) 90% or more of the total amountby volume of the laquinimod sodium particles have a size of 40 micronsor less, (ii) 50% or more of the total amount by volume of thelaquinimod sodium particles have a size of 15 microns or less, and (iii)10% or more of the total amount by volume of the laquinimod sodiumparticles have a size of 5 microns or less.

Laquinimod has bean graded as a highly potent API, demanding specialcaution and avoiding material contact with workers and environment.Laquinimod has been graded as having the highest potency rate,corresponding to a recommended acceptable daily intake (ADI) duringoperations and manufacturing of less than 0.01 mg/day or <1 μg/m³ as an8-hour TWA. High potency compounds are associated with controls, whetherengineering, administrative or procedure-related, that afford thedesired level of worker protection. For example, high potency compoundsmay require no human intervention or manual operations. (Bruce D.Naumann, Control Banding In The Pharmaceutical Industry,http://www.aioh.org.au/downloads/documents/ControlBankingBNaumann.pdf)

Importantly, although the mixture of the subject invention may be milledor unmilled, the present invention is achieved without the need of amilling operation.

The mixture of laquinimod sodium of the present invention overcomes thepotential problems associated with mixtures having large particles. Withrespect to processing and manufacturing, the small size of thelaquinimod sodium particles of the present invention may obviate theneed for milling and comminution steps. U.S. Pat. No. 7,884,208reflected the understanding in the art that there are problemsassociated with small particles in pharmaceutical compositions, but thelaquinimod sodium of the present invention has no problems associatedwith stability, processing or manufacturing.

Comminution introduces its own set of problems to a drug substancebeyond the disadvantages of introducing an additional drug processingstep. For example, milling can introduce impurities, new polymorphs,amorphous sections in the crystalline structure of the API, otherchanges to particle morphology, differences in agglomeration, increasedsolubility, changes in moisture levels, and changes in compressability(Hausner, “The Role of Particle Size in the Development of GenericProducts” 2003). As a result, comminution may affect the efficacy andsafety of a drug substance. Some of the disadvantages of comminution areillustrated by the side effects resulting from microcrystallineNitrofurantoin compared to macrocrystalline Nitrofurantoin, (Brumfitt,W. and J. M. T. Hamilton-Miller, J. Antimicrobial Chemotherapy42:363:371 (1998)).

Accordingly, it is advantageous to produce a drug substance which doesnot contain large particles to avoid the inefficiencies of additionalprocess steps such as milling or sieving. The laquinimod sodium of thepresent invention provides a mixture of laquinimod sodium particleshaving small particle sizes which avoids safety problems and additionalproblems related to milling.

Another concern during formulation processes is maintaining uniformityof content of the drug product. In the case of laquinimod, the unit doseof laquinimod is quite low relation to the total weight of the drugproduct, e.g., tablet or capsule. A typical formulation, for example,may comprise only a small amount of laquinimod, e.g., 0.3, 0.6 or 1.2mg, in a capsule with total weight of over 200 mg. As such, smallfluctuation in the amount of laquinimod due to problems of flowability,segregation, uniformity, or poor homogenous distribution could result ina large percent deviation from the desired amount, e.g., 0.3, 0.6 or 1.2mg. The mixture of laquinimod sodium of the present invention provideshigh uniformity of content and minimal fluctuations in the amount oflaquinimod in the capsules.

TABLE 1 Uniformity of Laquinimod Blend (UoB) and Uniformity of thecontent of filled capsules (UoC) Batch Batch type UoB AVG UoB RSD UoCUoC AV  1 C 99.5 1.67 99.3 4.5  2 C 100.6 0.61 98.7 2.7  3 C 102.6 1.1099.9 2.2  4 C 97.3 0.90 99.4 4.7  5 E 101.3 1.02 100.6 2.4  6 E 101.31.02 100.8 3.6  7 C 97.4 0.85 96.4 5.9  8 C 101.6 1.08 98.6 2.8  9 C98.5 0.71 94.2 8.6 10 (0.3 mg) C 101.2 0.66 96.9 8.7 11 C 101.2 0.6694.6 7.1 12 C 97.1 1.35 96.8 5 13 P 95.3 0.88 98.6 3.5 14 P 98.6 0.91101.4 5.2 15 P 97.1 0.59 96.6 5.7 16 P 98.8 0.58 98.4 5.3 17 P 98.2 0.5498.5 4.3 18 P 97.2 0.96 100.7 2.4 19 P 102.2 1.20 100.2 4.6 20 P 102.91.82 98.4 3.3 21 P 103.6 1.01 99.7 4.4 22 C 97.9 0.5 98.5 1.4 23 C 98.70.5 99.2 1.6 24A E 95.3 0.7 94.2 12.1 24B E 25 E 97.1 1.2 98 26A (0.6mg) E 99.8 1.8 97.4 2.2 26B (0.6 mg) E 99.8 1.8 97.4 2.2 UoB: Uniformityof Blend, RSD is the parameter to describe the uniformity before fillinginto capsules UoC: Uniformity of the content of the filled capsule, AVis the acceptance value is related to RSD to uniformity.

Uniformity of the shape of laquinimod particles is also an importantconcern during formulation as a lack of uniformity of shape can causevariation in density of drug substance and cause problems during drugproduct formation, e.g., capsule or tablet formation. Crystallinelaquinimod sodium particles are rod-shaped particles. It is known thatmilling operations may result in changes to particle shape.

Decreased particle size is known to result in faster dissolutionprofiles. The rate of dissolution of small particles is usually fasterthan that of large particles because a greater surface area of the drugsubstance is in contact with the liquid medium. When formulating a drugwith a low dissolution rate, it is desirable to decrease particle sizein order to increase dissolution and thus facilitate rapidgastrointestinal or oral absorption.

In such cases where drug substances have no recognized problemsassociated with dissolution rate, particle size reduction may beinadvisable and even deleterious. Increasing surface area can increasedegradation rates of the drug substance. As discussed, for example, inU.S. Pat. No. 8,178,127 and 7,989,473, laquinimod sodium is susceptibleto degradation.

Unexpectedly, in spite of known disadvantages associated with smallparticle sizes, it was found that an improved drug substance and drugproduct resulted from a mixture of crystalline laquinimod sodiumparticles wherein (i) 90% or more of the total amount by volume of thelaquinimod sodium particles have a size of 40 microns or less, (ii) 50%or more of the total amount by volume of the laquinimod sodium particleshave a size of 15 microns or less, and (iii) 10% or more of the totalamount by volume of the laquinimod sodium particles have a size of 5microns or less.

Accordingly, an advantage of the recrystallization process of thepresent invention is that the resulting mixture of crystallinelaquinimod sodium has particles having small particle sizes, which isassociated with high uniformity and homogeneity with respect todistribution of the API into capsules, tablets and other drug products.Laquinimod sodium crystals having small particle sizes can obviate orreduce the need for additional milling steps. The small particle sizesof the laquinimod sodium of the present invention are achieved withoutsacrificing desirable purity on density profiles and without the needfor prior milling operations.

Another advantage of the present invention is that laquinimod sodiumcrystals have a higher density than the laquinimod sodium crystalsproduced by the slurry-to-slurry process of U.S. Pat. No. 6,077,851. Lowtapped density is anathema to certain prized qualities in a drugsubstance of drug product such as compressibility, the ability of apowder to decrease in volume under pressure, and compactibility, theability of a powder to be compressed into a tablet of certain strengthor hardness. Crystals with low tapped density are also known to havepoor flowability, which results in a lack of uniformity of content infinished dosage forms, especially in tablets. (Rudnic et al. Chpt. 45,Remington's Pharmaceutical Sciences, 20^(th) Edition, LippincottWilliams & Wilkins, Baltimore, Md., (2000)) Uniformity of contest isespecially important for pharmaceutical compositions comprising a potentdrug substance, e.g., Laquinimod sodium.

Compared to the the slurry-to-slurry process of U.S. Pat. No. 6,077,851,the present invention also shows low aggregation of the particles and,additionally, provides particles with acceptable density and lowerlevels of impurities. As shown in FIGS. 5-8, the crude laquinimodresulting from the process described in U.S. Pat. No. 6,077,851 has ahigh rate or aggregates (FIGS. 5 and 6), compared to a low rate ofaggregates of the present invention (FIGS. 7 and 8).

Another advantage of the present invention is that the process of thepresent invention is environmentally friendly without sacrificingdesirable crystalline characteristics. Specifically, by use of water asthe primary solvent, the present invention achieves both environmentalfriendliness and improved crystalline characteristics, specifically withrespect to particle size distribution over U.S. Pat. No. 7,884,208.

Terms

As used herein, and unless stated otherwise, each of the following termsshall have the definition set forth below.

As used herein, “laquinimod” means laquinimod acid or a pharmaceuticallyacceptable salt thereof, including laquinimod sodium.

As used herein, “laquinimod acid” isN-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide,and its Chemical Registry number is 248281-84-7. “Laquinimod sodium” isthe sodium salt of laquinimod acid.

As used herein, D(0.1) is the particle size, in microns, below which 10%by volume distribution of the population is found.

As used herein, D(0.5) is the particle size, in microns, below which 50%by volume distribution of the population is found.

As used herein, D(0.9) is the particle size, in microns, below which 90%by volume distribution of the population is found.

As used herein, “crystalline characteristics” includes particle sizedistribution, bulk density and tapped density.

As used herein, “drug substance” refers to the active ingredient in adrug product or for use in a drug product, which providespharmacological activity or other direct effect in the diagnosis, cure,mitigation, treatment, or prevention of disease, or to affect thestructure or any function of the body of man or animals.

As used herein, “drug product” refers to the formulated or finisheddosage form containing the drug substance as well as at least onepharmaceutically acceptable carrier.

As used herein, a composition that is “free” of a chemical entity meansthat the composition contains, if at all, an amount of the chemicalentity which cannot be avoided although the chemical entity is not partof the formulation and was not affirmatively added during any part ofthe manufacturing process. For example, a composition which is “free” ofan alkalizing agent means that the alkalizing agent, if present at all,is a minority component of the composition by weight. Preferably, when acomposition is “free” of a component, the composition comprises lessthan 0.1 wt %, 0.05 wt %, 0.02 wt %, or 0.01 wt % of the component.

As used herein, “dissolution rate” is determined based on the amount ofdrug substance dissolved in 30 min. as indicated in the U.S.Pharmacopeia <711>.

As used herein, “atmospheric pressure” refers to a pressure of about 1atm.

As used herein, “ambient temperature” refers to a temperature of about20° C. to about 30° C.

As used herein, “about” in the context of a numerical value or rangemeans ±10% of the numerical value or range recited or claimed.

As used herein, “approximately” in the context of a numerical value orrange means ±5% of the numerical value or range recited or claimed.

The term “stable pharmaceutical composition” as used herein inconnection with the composition according to the invention denotes acomposition, which preserves the physical stability/integrity and/orchemical stability/integrity of the active pharmaceutical ingredientduring storage. Furthermore, “stable pharmaceutical composition” ischaracterized by its level of degradation products not exceeding 5% at40° C./75% RH after 6 months or 3% at 55° C./75% PH after two weeks,compared to their level is time zero.

As used herein, “treating” and “treatment” encompasses, e.g., inducinginhibition, regression, or stasis of a disease, disorder or condition,or ameliorating or alleviating a symptom of a disease, disorder orcondition. “Ameliorating” or “alleviating” a condition or state as usedherein shall mean to relieve or lessen the symptoms of that condition orstate. “Inhibition” of disease progression or disease complication in asubject as used herein means preventing or reducing the diseaseprogression and/or disease complication in the subject.

“Administering to the subject” means the giving of, dispensing of, orapplication of medicines, drugs, or remedies to a subject to relieve,cure, or reduce the symptoms associated with a condition, e.g., apathological condition.

The drug substance of the present invention, e.g., laquinimod sodium,may be administered in admixture with suitable pharmaceutical diluents,extenders, excipients, or carriers (collectively referred to herein as apharmaceutically acceptable carrier) suitably selected with respect tothe intended form of administration and as consistent with conventionalpharmaceutical practices. The unit will be in a form suitable for oral,rectal, topical, intravenous or direct injection or parenteraladministration. The compounds can be administered alone or mixed with apharmaceutically acceptable carrier.

This carrier can be a solid or liquid, and the type of carrier isgenerally chosen based on the type of administration being used. Theactive agent can be co-administered in the form of a tablet or capsule,liposome, as an agglomerated powder or in a liquid form. Examples ofsuitable solid carriers include lactose, sucrose, gelatin and agar.Capsules or tablets can be easily formulated and can be made easy toswallow or chew; other solid forms include granules, and bulk powders.

Capsules or tablets may contain suitable binders, lubricants,disintegrating agents, diluents, coloring agents, flavoring agents,flow-inducing agents, and melting agents. For instance, for oraladministration in the dosage unit form of a tablet or capsule, theactive drug component can be combined with an oral, non-toxic,pharmaceutically acceptable, inert carrier such as lactose, gelatin,agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.

Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like.

Lubricants used in these dosage forms include sodium oleate, sodium,stearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, and the like.

Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

Examples of suitable liquid dosage forms include solutions orsuspensions in water, pharmaceutically acceptable fats and oils,alcohols or other organic solvents, including esters, emulsions, syrupsor elixirs, suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Such liquid dosage forms may contain, forexample, suitable solvents, preservatives, emulsifying agents,suspending agents, diluents, sweeteners, thickeners, and melting agents.

Oral dosage forms optionally contain flavorants and coloring agents.Parenteral and intravenous forms may also include minerals and othermaterials to make them compatible with the type of injection or deliverysystem chosen.

The compounds used in the method of the present invention may also beadministered in the form of liposome delivery systems, such as smallunilamellar vesicles, large unilamellar vesicles, and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids, suchas cholesterol, stearylamine, or phosphatidylcholines. The compounds maybe administered as components of tissue-targeted emulsions.

The compounds used in the method of the present invention may also becoupled to soluble polymers as targetable drug carriers or as a prodrug.Such polymers include polyvinylpyrrolidone, pyran copolymer,polyhydroxylpropylmethacrylamide-phenol,polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polyglycolicacid, copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacylates, and crosslinked or amphipathicblock copolymers of hydrogels.

For oral administration in liquid dosage form, the oral drug componentsare combined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Examples ofsuitable liquid dosage forms include solutions or suspensions in water,pharmaceutically acceptable fats and oils, alcohols or other organicsolvents, including esters, emulsions, syrups or elixirs, suspensions,solutions and/or suspensions reconstituted from non-effervescentgranules and effervescent preparations reconstituted from effervescentgranules. Such liquid dosage forms may contain, for example, suitablesolvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, thickeners, and melting agents.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance. In general, water, a suitableoil, saline, aqueous dextrose (glucose), and related sugar solutions andglycols such as propylene glycol or polyethylene glycols are suitablecarriers for parenteral solutions. Solutions for parenteraladministration preferably contain a water soluble salt of the activeingredient, suitable stabilizing agents, and if necessary, buffersubstances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkoninm chloride, methyl- or propyl-paraben, and chlorobutanol.Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetest in this field.

The drug substance of the present invention, e.g., laquinimod sodium,may be administered in various forms, including those detailed herein.The treatment with the compound may be a component of a combinationtherapy or an adjunct therapy, i.e. the subject or patient in need ofthe drug is treated or given another drug for the disease in conjunctionwith one or more of the instant compounds. This combination therapy canbe sequential therapy where the patient is treated first with one drugand then the other or the two drugs are given simultaneously. These canbe administered independently by the same route or by two or moredifferent routes of administration depending on the dosage formsemployed.

Gelatin capsules may contain the active ingredient compounds andpowdered carriers, such as lactose, starch, cellulose derivatives,magnesium stearate, stearic acid, and the like. Similar diluents can beused to make compressed tablets. Both tablets and capsules can bemanufactured as immediate release products or as sustained releaseproducts to provide for continuous release of medication over a periodof hours. Compressed tablets can be sugar coated or film coated to maskany unpleasant taste and protect the tablet from the atmosphere, orenteric coated for selective disintegration in the gastrointestinaltract.

The compounds used in the method of the present invention may also beadministered in intranasal form via use of suitable intranasal vehicles,or via transdermal routes, using those forms of transdermal skin patcheswell known to those of ordinary skill in that art. To be administered inthe form of a transdermal delivery system, the dosage administrationwill generally be continuous rather than intermittent throughout thedosage regimen.

Parenteral and intravenous forms may also include minerals and othermaterials to make them compatible with the type of injection or deliverysystem chosen.

A dosage unit of the compounds used in the method of the presentinvention may comprise a single compound or mixtures thereof withadditional antibacterial agents. The compounds can be administered inoral dosage forms as tablets, capsules, pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions. The compoundsmay also be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous, or intramuscular form, or introduceddirectly, e.g. by injection, topical application, or other methods, intoor onto a site of infection, all using dosage forms well known to thoseof ordinary skill in the pharmaceutical arts.

A “dose” or “dosage unit” of laquinimod as measured in milligrams refersto the milligrams of laquinimod acid present in a preparation,regardless of the form of the preparation. A dosage unit may comprise asingle compound or mixtures of compounds thereof. A dosage unit can beprepared for oral dosage forms, such as tablets, capsules, pills,powders, and granules. For example, the “dose” or “dosage unit” oflaquinimod may be 0.3, 0.6, or 1.2 mg.

As used herein, a “pharmaceutically acceptable” component is one that issuitable for use with humans and/or animals without undue adverse sideeffects (such as toxicity, irritation, and allergic response)commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable carrier” refers to acarrier or excipient that is suitable for use with humans and/or animalswithout undue adverse side effects (such as toxicity, irritation, andallergic response) commensurate with a reasonable benefit/risk ratio. Itcan be a pharmaceutically acceptable solvent, suspending agent orvehicle, for delivering the instant compounds to the subject. Thecarrier may be liquid or solid and is selected with the planned mannerof administration in mind. “Pharmaceutically acceptable carrier”includes “fillers”, which fill out the size of a tablet or capsule,making it practical to produce and convenient for the consumer to use.By increasing the bulk volume, the fillers make it possible for thefinal product to have the proper volume for patient handling,“Pharmaceutically acceptable carrier” also includes “lubricants”, whichprevent ingredients from clumping together and from sticking to thetablet punches or capsule filling machine. Lubricants also ensure thattablet formation and ejection can occur with low friction between thesolid and die wall. “Pharmaceutically acceptable carrier” also includesinert carriers such as lactose, gelatin, agar, starch, sucrose, glucose,methyl cellulose, dicalcium phosphate, calcium sulfate, mannitol,sorbitol, microcrystalline cellulose and the like. Liposomes are also apharmaceutically acceptable carrier.

It is understood that where a parameter range is provided, all integerswithin that range, and tenths and hundredth thereof, are also providedby the invention. For example, “0.15-0.35%” includes 0.15%, 0.16%, 0.17%etc. up to 0.35%.

The subject invention is also intended to include all isotopes of atomsoccurring on the compounds disclosed herein, including impurities.Isotopes include those atoms having the same atomic number but differentmass numbers. By way of general example and without limitation, isotopesof hydrogen include tritium and deuterium. Isotopes of carbon includingC-13 and C-14.

A “detection limit” for an analytical method used in screening ortesting for the presence of a compound in a sample is a threshold underwhich the compound in a sample cannot be detected by the analyticalmethod used. For example, the detection limit of a given method fordetecting5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(MCQCA) is 0.03% and the detecting limit of a given method for detectingmethyl5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate(MCQME), 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ),5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate(MCQEE) and unknown impurities is 0.02%

As need herein, “density” is a measurement defined as the mass of asubstance per unit volume.

As used herein, “bulk density” or “BD” refers to a density measurementof a loose, uncompacted substance, wherein the volume of the substanceincludes the air trapped between particles.

As used herein, “tapped density” or “TD” refers to a density measurementof a substance that has been tapped or vibrated, thus minimizing thevolume of the substance by eliminating or minimizing the air trappedbetween particles.

As used herein, “rapid stirring” refers to stirring which splashessolvent onto the walls of the vessel.

As used herein, “blend uniformity” refers to the homogeneity of blend orgranulate including laquinimod sodium particles prior to encapsulation,tableting or otherwise finalizing the drug product beyond formation ofthe final blend, and can represent either one sample or the average ofmore than one sample. Blend uniformity may be measured, for example, bytaking 10 samples that represent the upper, middle and lower layer ofeach batch of the final blend, performing an HPLC assay to measure theamount of active ingredient in the samples, and comparing the amount ofactive ingredient in each sample to the labeled amount of activeingredient. The standard deviation and relative standard deviation canbe determined based on the individual amounts of the tested samplesexpressed as percentages of the labeled amount of drug substance in eachsample.

As used herein, “content uniformity” refers to the homogeneity of thelaquinimod sodium content among dosage forms, e.g., capsules or tablets,after formulation. The uniformity of dosage units by content uniformityof the pharmaceutical composition described herein meets the U.S.Pharmacopeia <905> Acceptance Value and range (as specified); L₁=15.0and L₂=25.0. Consent uniformity may be measured, for example, asindicated by the United States Pharmacopoeia which includes 1) assayingten tablets (or other dosage form of the drug product) to ensure thatthe relative standard deviation (RSD) of active content is less than orequal to 6.0% and no value is outside 85-115%; and 2) assaying twentymore tablets (or other dosage form of the drug product) to ensure thatthe RSD for all thirty is less than or equal to 7.8%, no more than onevalue is outside 85-115% and no value is outside 75-125% of statedcontent.

As used herein, “residual solvents” include ethanol, n-heptane,n-octane, methanol, acetone, dioxane, and dimethyl formamide. Residualsolvents may be determined, for example, based on the manufacturer'sstatements of residual solvent levels in the activeingredients/excipients and calculation as per U.S. pharmacopeia <467>Option 2, product meets the USP <467> Residual Solvents limit criteria.Testing is not necessarily required.

As used herein, “NMT” means no more than.

As used herein, “MCQME” means methyl5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate.MCQME is disclosed in U.S. Pat. No. 7,560,557. MCQME has the structure:

As used herein, “MCQEE” means ethyl5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylateMCQEE is disclosed in U.S. Pat. No. 7,560,557. MCQEE has the structure:

As used herein, “MCQ” means5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline. MCQ is disclosedin U.S. Pat. No. 7,560,557. MCQ has the structure:

As used herein, “MCQCA” means5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylicacid. MCQCA is disclosed in U.S. Pat. No. 7,560,557. MCQCA has thestructure:

As used herein, “NEA” means N-ethyl aniline. NEA is disclosed in U.S.Pat. No. 7,560,557. NEA has the structure:

As used herein, “5-HLAQ” meansN-ethyl-4,5-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydroquinoline-3-carboxamide.5-HLAQ is disclosed in PCT International Application No. PCT/US13/26476.5-HLAQ has the structure:

As used herein, “3-HLAQ” means5-chloro-N-ethyl-3-hydroxy-1-methyl-5-2,4-dioxo-N-phenyl-1,2,3,4-tetrahydroquinoline-3-carboxamide.3-HLAQ is disclosed in PCT International Application No.PCT/US2000/013890. 3-HLAQ has the structure:

As used herein, “MEG-LAQ” meansN-ethyl-4-hydroxy-1-methyl-5-(methyl(2,3,4,5,6-pentahydroxyhexyl)amino-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide.MEG-LAQ is disclosed in U.S. Provisional Application No. 61/644,054.MEG-LAQ has the structure:

As used herein, “DELAQ” means5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide.DELAQ is disclosed in PCT International Application No.PCT/US2011/043391. DELAQ has the structure:

As used herein, “INBA” means2-Chloro-6-(1-ethyl-N-methyl-2-oxoindoline-3-carboxamido)benzoic acid.INBA is disclosed in PCT International Application No.PCT/US2008/013890. INBA has the structure:

As used herein, “SPIRO-LAQ” means1H,3H-spiro(5-chloro-1-methylquinoline-2,4-dione-3,3′-[1]ethylindolin-[2]-one).SPIRO-LAQ is disclosed in PCT International Application No.PCT/US2008/013890. SPIRO-LAQ has the structure:

As used herein, “DMM” means dimethylmalonate. DMM is a syntheticreagent, and has the structure:

As used herein, “DMS” means Dimethyl sulfate. DMS is a syntheticreagent.

Potential impurities/degradation products are further described in Table2.

TABLE 2 Potential Impurities/Degradation Products Potential Impurity/Specification Specification Degradation in Drug Limits in Drug ProductStructure Definition Substance Product MCQ 5-Chloro-4- hydroxy-1-methylquinolin- 2(1H)-one

Synthetic impurity, potential degradant NMT 0.15% NMT 0.5% for sum ofMCQ and MCQCA MCQCA 5-Chloro-4- hydroxy-1- methyl-2-oxo- 1,2-dihydro-quinoline-3- carboxylic acid

Synthetic impurity, potential degradant NMT 0.15% NMT 0.5% for sum ofMCQ and MCQCA MCQME Methyl 5- chloro-4- hydroxy-1- methyl-2-oxo-1,2-dihydro- quinoline-3- carboxylate

Synthetic impurity NMT 0.15% — NEA N-Ethylaniline

Synthetic impurity, potential degradant NMT 0.10% — MCQEE Ethyl5-chloro- 4-hydroxy-1- methyl-2-oxo- 1,2-dihydro- quinoline-3-carboxylate

Synthetic impurity NMT 0.10% — 5-HLAQ N-Ethyl-4,5- dihydroxy-1-methyl-2-oxo- N-phenyl-1,2- dihydro- quinoline-3- carboxamide

Synthetic impurity, potential photo- degradant NMT 0.10% NMT 0.5% DELAQ5-Chloro-4- hydroxy-1- methyl-2-oxo- N-phenyl-1,2- dihydro- quinoline-3-carboxamide

Synthetic impurity NMT 0.1% — LAQ 5-Chloro-N- ethyl-4- hydroxy-1-methyl-2-oxo- N-phenyl-1,2- dihydro- quinoline-3- carboxamide

Synthetic impurity, potential degradant, active moiety NMT 1.0% —SPIRO-LAQ 1H,3H-spiro[5- chloro-1- methylquinoline- 2,4-dione-3,3′-[1]ethylindolin- [2]-one]

Potential oxidation product — — INBA 2-Chloro-6-(1- ethyl-N-methyl-2-oxoindoline- 3-carboxamido) benzoic acid

Potential secondary degradation product (degradation of SPIRO-LAQ) — —3-HLAQ 5-Chloro-N- ethyl-3- hydroxy-1- methyl-2,4- dioxo-N-phenyl-1,2,3,4- tetrahydro- quinoline-3-

Potential oxidation product — — carboxamide DMM Dimethyl malonate

Synthetic impurity (residual reagent) NMT 1.0% — DMS — Syntheticpotentially NMT 1 ppm — Dimethyl genotoxic impurity sulfate (residualreagent) MEG-LAQ N-ethyl-4- hydroxy-1- methyl-5- (2,3,4,5,6-pentahydroxy- hexylamino)-2- oxo-N-phenyl- 1,2- dihydroquinoline- 3-carboxamide

Potential DP impurity/degradation product (adduct of laquinimod sodiumwith one of the excipients (meglumine)) — NMT 1.0% DS = drug substance;DP = drug product

Impurities are measured by common pharmacopeial methods unless otherwisespecified.

As used herein, an “anti-solvent” is a solvent in which laquinimodsodium is slightly soluble, very slightly soluble, practicallyinsoluble; or insoluble at room temperature (20-25° C.). The solubilityterms are defined below, in accordance with the United StatesPharmacopoeia XXV.

Parts of solvent required for 1 Term part solute Slightly soluble From100 to 1000 Very slightly soluble From 1000 to 10,000 Practicallyinsoluble 10,000 and over Insoluble 10,000 and over

Specific examples of the techniques, pharmaceutically acceptablecarriers and excipients that may be used to formulate oral dosage formsof the present invention are described, e.g., in U.S. Pat. No.7,589,208. For example, the oral dosage form of the present inventionmay comprise an alkaline-reacting component, said component preferablyamounting from about 1 to 20% by weight of the formulation in order tokeep the pH above 8.

Techniques and compositions for making dosage forms useful in thepresent invention are described in the following references: 7 ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel,Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976);Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company,Easton, Pa., 1985); Advances in Pharmaceutical Sciences (DavidGanderton, Trevor Jones, Eds., 1992); Advances in PharmaceuticalSciences Vol. 7. (David Ganderton, Trevor Jones, James McGinity, Eds.,1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugsand the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs andthe Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); DrugDelivery to the Gastrointestinal Tract (Ellis Horwood Books in theBiological Sciences. Series in Pharmaceutical Technology; J. G. Hardy,S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and thePharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T.Rhodes, Eds.). All of the aforementioned publications are incorporatedby reference herein.

The purification of impure crystalline compounds is usually attained byrecrystallization from a suitable solvent or mixture of solvents.(Vogel's Textbook of Practical Organic Chemistry, 5^(th) edition.Longman Scientific & Technical, 1989.) The recrystallization processgenerally comprises the following steps: a) dissolving the impurecrystalline substance in a suitable solvent near the boiling point; b)filtering the hot solution from particles of insoluble material anddust; c) allowing the hot solution to cool to cause the dissolvedsubstance to crystallize out; and d) separating the crystals from thesupernatant solution. (Id.) However, standard recrystallizationtechniques were accompanied by low or no yields when applied tolaquinimod sodium as taught in U.S. Pat. No. 7,884,208. As shown inExamples 2-7 of U.S. Pat. No. 7,884,208, attempts to recrystallizelaquinimod sodium using standard recrystallization procedures resultedin poor yields, if any. The process of U.S. Pat. No. 7,884,208 overcomesthe difficulties associated with recrystallizing laquinimod sodium byuse of an anti-solvent in which laquinimod sodium is practicallyinsoluble. In addition, the process of U.S. Pat. No. 7,884,208concentrates the laquinimod sodium aqueous solution before the additionof the anti-solvent. The process of the present invention is animprovement over the process of U.S. Pat. No. 7,884,208.

This invention will be better understood by reference to theExperimental details which follow, but those skilled in the art willreadily appreciate that the specific experiments detailed are onlyillustrative of the invention as described more fully in the claimswhich follow thereafter.

Experimental Details Determination of Powder Density Bulk Density

1. Mix powder;

2. Tare a 50 ml empty cylinder on a 0.02 g sensitivity balance;

3. Transfer the powder, without compacting, to the cylinder being heldat approximately a 45 degree angle to achieve an untapped apparentvolume of 40 to 50 ml.

4. Bring the cylinder containing the sample to a vertical position by asharp move in order to level the volume for reading.

5. Read the apparent volume (Va) to the nearest graduated unit;

6. Weigh the cylinder with sample (the balance gives sample weight M);

7. Calculate bulk density in g/ml according to the following equation:BD=M/Va;

8. Perform steps 1-7 again and report the average data of duplicates.

Tapped Density

1. Put the same cylinder used to calculate Bulk Density in aQuantachrome Dual Autotap Instrument;

2. Perform 1250 taps;

3. Read the tapped volume (Vf) to the nearest graduated unit;

4. Calculate the tapped density in g/ml according to the followingequation: TD=M/Vf;

5. Perform steps 1-4 again and report the average data of duplicates.

Determination of Particle Size

The particle size distributions were measured by Malvern LaserDiffraction, using the Mastersizer S model. Laser diffraction relies onthe fact that diffraction angle of light is inversely proportional toparticle size. Properties of particles are measured and interpreted asmeasurements of a sphere (a sphere being the only shape that can bedescribed by one unique number). In addition, laser diffractioncalculates a particle size distribution based around volume terms, thuseliminating particle count from the determination of particle size. TheMastersizer S model measures particles using a single technique and asingle range setting.

D(0.1) is the particle size, in microns, below which 10% by volumedistribution of the population is found. D(0.5) is the particle size, inmicrons, below which 50% by volume distribution of the population isfound. D(0.9) is the particle size, in microns, below which 90% byvolume distribution of the population is found.

Determination of Heavy Metals

Metal content was measured using inductively coupled plasma atomicemission spectrometry using an inductively coupled plasma atomicemission spectrometry (“ICP-AES”) system manufactured by Spectre (Kieve,Germany). Sample digestion was performed in 65% nitric acid, and theinternal standard used was scandium.

Note: In the following examples the volumes of solvents used arecalculated relative to starting weight of laquinimod sodium. The yieldsare calculated in weight percent.

Determination of Purity

Laquinimod sodium and polar impurity/degradation products weredetermined by isocratic reversed phase high performance liquidchromatography (RP-HPLC), using an ODS-3V column and a mobile phasecomprised of a mixture of ammonium acetate buffer at pH 7.0 (80%) andacetonitrile (20%). The detection technique was ultraviolet absorptionat 240 nm.

Specific HPLC Conditions:

Column & Packing: Inertsil ODS-3V, 5 μm, 4.6×250 mm, GL Sciences Inc.

Guard column: Opti-Guard C10, 1×10 mm

Mobile phase: Acetonitrile: Buffer pH 7.0-20:80 (v/v). Mix and degas

Buffer pH 7.0 preparation: Dissolve 7.7 g Ammonium acetate in 2000 waterand adjust to pH 7.0±0.05 with aqueous ammonia or glacial acetic acid.Filter through a 0.45 μm membrane filter.

Flow rate: 1.5 mL/min

Detection: UV at 240 nm

Injection volume: 50 μL

Diluent A: Acetonitrile/Water—50:50 (v/v)

Diluent B (and blank): Mobile Phase

Column temperature: 40° C.

Autosampler temperature: 5° C.

Run time: 40 minutes

Typical HPLC Procedure: 1. Standard Solutions Preparation 1.1 LaquinimodStandard Stock Solution (Solution S)

Weigh accurately in duplicate about 15 mg of laquinimod sodium standardinto a 50 ml volumetric flask. Dilute with diluents A up to ⅔ of thevolume, sonicate for 2 minutes in a cold sonication bath and dilute tovolume with diluents A.

Concentration of standard stock solution is about 380 μg/mL laquinimodsodium. Standard stock solution may be used for one month when stored ina refrigerator 2° C.-8° C.

1.2 Laquinimod Standard Working Solution for Assay (Solution A)

Dilute 3 mL of the Standard Stock Solution to 10 mL with diluents B(dilution factor 3.33).

Concentration of Laquinimod sodium is about 90 μg/mL. Concentrationexpressed as laquinimod (acid) is about 85 μg/mL.

Standard working solution A may be used for 7 days when stored in arefrigerator (2° C.-8° C.)

1.3 Standard Stock Solution

Weigh accurately about 18 mg of MCQCA standard into a 100 mL volumetricflask. Dilute to volume with acetonitrile, sonicate (in a coldsonication bath) until the substance is completely dissolved—stock MCQCAsolution.

Concentration of MCQCA is about 180 μg/mL.

MCQCA Stock standard solution should be freshly prepared.

1.4 Standard Solution for Determination of Impurities (Solution I)

Prepare a solution in diluents B, containing Laquinimod in aconcentration of 0.2% and MCQCA—in a concentration of 0.1%, with respectto the working concentration of Laquinimod in Standard solution A. As anexample, apply the following procedure.

Transfer 4.0 mL of laquinimod sodium standard solution for assay(Solution A; and 1.0 mL of MCQCA stock standard solution to a 100 mLvolumetric flask and dilute to volume with the diluents B (intermediatedilution).

Place 2.5 mL of this intermediate dilution into a 50 mL volumetric flaskand make up to volume with diluents B.

Total dilution factor for laquinimod standard is 1666.67, for MCQCA2000.

Concentration of laquinimod sodium is about 0.18 μg/mL (0.2%)

Concentration of MCQCA is about 0.09 μg/mL (0.1%, QL level).

Standard solution I may be used for 24 hours when stored in arefrigerator.

2. Resolution Solutions Preparation 2.1 Mixed Solution

Prepare solution containing the following potential impurities standards(markers) using the Diluent A as a solvent:

Mixed Solutition:

-   MCQ: 5-Chloro-4-hydroxy-1-methylquinolin-2(1H)-one-   MCQCA:    50Chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic    acid-   MCQMA: Methyl    5-Chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate-   5-HLAQ:    N-Ethyl-4,5-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide

The Mixed Solution may be prepared as follows:

Weigh about 3 mg of each impurity standard/marker into a 100 mLvolumetric flask, dissolve (sonication is acceptable) and dilute tovolume with the Diluent A.

Concentration of each impurity in the Mixed Solution is about 30 μg/mL.Mixed Solution may be used for up to 4 months when stored frozen atabout −20° C. For this purpose, the freshly prepared Mixed Solutionshould be divided into aliquots, immediately frozen and stored at −20°C. After thawing, the aliquots should be mixed well and should not berefrozen.

2.2 Stock Solutions of Additional Impurities

Weigh about 3 mg of MCQEE (Ethyl5-Chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate)into a 100 mL volumetric flask, dissolve (sonication is acceptable) anddilute to volume with the Diluent A. This is MCQEE Stock solution.

This solution may be used for up to 4 months when stored frozen at about−20° C.

For this purpose, the freshly prepared MCQEE Stock Solution should bedivided into aliquot, immediately frozen and stored at −20° C. Afterthawing, the aliquots should be mixed well and should not be refrozen.

Weigh about 3 mg of MEG-LAQ (Meglumine Adduct of Laquinimod) into a 100mL volumetric flask, dissolve (sonication is acceptable) and dilute tovolume with the Diluent A. This is MEG-LAQ Stock solution.

This solution may be used for one week when stored in refrigerator (2°C.-8° C.).

2.3 Resolution Solutions

Prepare two Resolution Solutions separately as follows, using the MixedSolution.

2.3.1 Resolution Solution 1

Transfer 3 mL of laquinimod standard stock solution (solution S), 0.3 mLof the Mixed Solution and 0.3 mL of the MCQEE Stock solution to a 10 mLvolumetric flask and dilute to volume with the Diluent B. This isResolution Solution 1.

Concentration of laquinimod sodium in it is about 90 μg/mL.Concentration of each impurity—is about 0.9 μg/mL (about 1% with respectto the working concentration of laquinimod).

Resolution Solution 1 is used for resolution test (for systemsuitability: and for determination of retention times (RT)/relativeretention times (RRT) of five impurities: MCQ, MCQCA, MCQME, MCQEE, and5-HLAQ.

Resolution Solution 1 may be used for 9 days if stored in a refrigerator2° C.-8° C.).

2.3.2 Resolution Solution 2

Transfer 3 mL of laquinimod standard stock solution (solution S), 0.3 mLof the Mixed Solution and 0.3 mL of the MEG-LAQ Stock solution to a 10mL volumetric flask and dilute to volume with the Diluent B. This isResolution Solution 2.

Concentration of laquinimod sodium in it is about 90 μg/mL.Concentration of each impurity—is about 0.9 μg/mL (about 1% with respectto the working concentration of laquinimod).

Resolution Solution 2 is used for determination of retention time ofMEG-LAQ.

Resolution Solution 2 may be used for 9 days if stored in a refrigerator2° C.-8° C.).

3. Sample Solution Preparation

Weigh accurately 20 capsules and completely empty their contents into amortar. Pay attention to complete emptying of capsule contents into themortar, using spatula when necessary. Weigh the empty capsules.Calculate the average weight of the capsule contents. Mix and grind thecapsule contents in a mortar and keep the ponder in a tightly closedcontainer protected from light.

Weigh accurately, in duplicate, the amount of powder corresponding to 7capsules, into a 50 mL volumetric flask.

Add diluents B up to ⅔ of the volume, shake for 30 minutes at 200mot/min. Dilute to volume with Diluent B. Mix well. Filter before usethrough a 0.45 μm GHP ACRODISC GF filter or equivalent, discarding thefirst 0.5-1 mL.

Working concentration of laquinimod (acid) in about 84 μg/mL.Immediately after preparation place sample solutions into a refrigeratoror in a cooled to 5° C. autosampler. The sample solutions may be usedfor 24 hours when kept at the temperature 2° C.-8° C.

4. Procedure

Inject the Resolution Solutions, Diluent B (Blank), Standard Solutionsfor assay and IDD and Sample solutions, according to standard operatingprocedures.

Determine the retention time (RT) and the area of the laquinimod peak inthe chromatograms of Sample and Standard Solutions for identificationand assay.

Determine the RT, the relative retention time (RRT) and peak areas ofall known impurities and any other impurities in the chromatograms ofSample Solutions, for calculation of the content ofimpurities/degradation products.

Ignore early elution peaks of excipients and system peaks (Seechromatogram for determination of impurities/degradation products). Forexample, Use integration inhibition between 0 and RRT 0.15 (about 2.5minutes).

Adjust integration parameters to reject peaks with area less than 10% ofthe average response of Laquinimod peak in the injections of StandardSolution I (for determination of impurities/degradation products).

Disregard peak of MEG-LAQ in sample injections (identified followingResolution Solution 2). The content of MEG-LAQ is tested by a differentmethod.

5. System Suitability Test

5.1 Resolution Test

Typical retention time of laquinimod peak is 15.5±2.0 minutes.

Tailing factor (USP) for laquinimod peak should be not more than 2.0.

Resolution factor for all the pairs of peaks should be not less than(NLT) 2.

RRT of the peaks of known impurities/degradation products should be asfollows:

-   MCQME: 0.33-0.38-   MCQ: 0.49-0.58-   MCQEE: 0.56-0.65-   MCQCA: 0.71-0.85-   5-HLAQ: 1.2-1.4 (Should not be more than 23 minutes)

MEG-LAQ peak is substantially broadened in comparison with neighboringpeaks. Retention time of MEG-LAQ is variable, being very sensitive toslightest changes in chromatographic conditions (pH, % acetonitrile,Temperature, etc.) and therefore should be defined using its peak in thechromatogram of the Resolution Solution 2. Typically, its RRT is about0.66.

5.2 System Precision Test

Evaluate laquinimod standards for assay and IDD in order to test thesystem precision according to the standard operating procedures.

MCQCA in Solution I is used to test the sensitivity of the system. RSDof the area of six injections of Std 1 as well as the difference betweenStd 1 and Std 2 should be no more than (NMT) 20%.

5.3 Blank

Injection diluents B to detect system peaks.

6. Identification by Retention Time (RT)

The RT of the main peak obtained in the sample chromatogram shouldcorrespond to that obtained for the laquinimod peak in the injection ofStandard Solution.

7. Calculation and Report 7.1 Assay Calculation

${\% \mspace{14mu} {Assay}\mspace{14mu} ( {{to}\mspace{14mu} {Label}\mspace{14mu} {Claim}} )} = \frac{{Area}_{Smp} \times {Conc}_{Std} \times 0.94 \times V_{Smp} \times {AvgWt}_{CapsContent}}{{Area}_{Std} \times W_{Smp} \times {Label}\mspace{14mu} {Claim}}$

Where 0.94 is the conversion factor of laquinimod sodium salt tolaquinimod (acid).

7.2 Calculation and Evaluation of Impurities/Degradation Products

7.2.1 Calculation of Relative Retention Time (RRT)

${{RRT}\mspace{14mu} {Impurity}} = \frac{{RT}\mspace{14mu} {Impurity}}{{RT}\mspace{14mu} {Laquinimod}}$

7.2.2. Calculation of Content of Impurities/Degradation Products

${\% \mspace{14mu} {Impurity}} = \frac{{Area}_{impurity} \times {Conc}_{Std} \times V_{Smp} \times {AvgWt}_{CapsContent} \times 0.94 \times {RRF}}{{Area}_{Std} \times W_{Smp} \times {Label}\mspace{14mu} {Claim}}$

Area_(impurity) is the area of an impurity/degradation product (known orunknown) peak in the Sample Solution.

Area_(std) is the laquinimod peak in chromatogram at Standard SolutionI.

0.94 is the conversion factor of laquinimod sodium salt to laquinimod(acid).

RRF is the relative response factors of impurities/degradation productscalculated as the following ratio: slope of Laquinimod regressionline/slope of impurity regression line.

The values for relative response factors with respect to laquinimod are:MCQME: 0.74; MCQ: 0.65; MCQEE: 0.85; MCQCA: 0.62; and 5-HLAQ: 1.0.

RRF for unknown impurities/degradation products is taken as 1.0.

7.2.3 Evaluation and Report of Impurities/Degradation Products

Quantitation level (QL) MCQME, MCQ, MCQEE, 5-HLAQ, and unknownimpurities is 0.05%. Detection level (DL) of MCQME, MCQ, MCQEE, 5-HLAQand unknown impurities is 0.02%. QL of MCQCA is 0.1%. Detection level DLof MCQCA is 0.03%.

Correlate all the peaks in sample chromatogram with those in the systemsuitability chromatogram, with ±5% of the actual corresponding retentiontimes. Report data as shown is Table 3.

TABLE 3 Reporting Guidelines for HPLC data Result Report Specifiedimpurities 5-HLAQ ≧0.05% The calculated result  <0.05% <0.05% <0.02% (orND) <0.02% MCQ and MCQCA ≧0.01% The calculated result sum  <0.01% <0.01%<0.03% (or ND) <0.03% Other impurities MCQME, MCQEE ≧0.05% Thecalculated result  <0.05% <0.05% <0.02% (or ND) <0.02% Unknown peaks≧0.05% The calculated result (by RRT to  <0.05% <0.05% laquinimod)<0.02% (or ND) Not to be reported* Total ≧0.05% The sum of  <0.05% (or<0.02% of ND) calculated results <0.05% *If no impurities were detected,report: any other <0.2%.

TABLE 4 Example System Suitability Results 1 USP RT Reso- USP Int NameRT Ratio Area lution Trailing Type 1 MCQME 5.460 0.36 35801 1.07 BB 2MCQ 8.260 0.54 60687 8.2 1.16 BV 3 MCQEE 9.249 0.6 24029 2.6 1.05 VB 4MCQCA 12.031 0.78 18609 5.7 1.34 BB 5 Laquinimod 15.332 12332469 5.21.84 BB 6 5-HLAQ 20.451 1.33 89463 7.3 1.04 BB

EXAMPLE 1 Modified Recrystallization of Laquinimod Sodium—PilotProduction, 100 Fold Scale-Up, (Pilot Scale Batches A and B)

Re-crystallization of Laquinimod Na on pilot scale is performed in twoglass-lined reactors (Reactor A, 30 liter volume and Reactor B 60liter). Solid product is filtered and dried in Hastelloy C agitatedfilter-dryer with 20 micron mesh.

Batch size is 2.5 kg of starting crude Laquinimod Na.

Batch of crude Laquinimod Na (2.5 kg) is introduced to Reactor A with 10volumes of process water. The batch is heated to 60-73° C. at stirringuntil complete dissolution of solid.

The hot solution in Reactor A is transferred to Reactor B through 0.2 μmfiltration system. Reactor A and filters washed with 1.2 volumes ofprocess water and the wash is transferred to the Reactor B.

Vacuum is built-up and the solution in the Reactor B is evaporated atP<45 mmHg and jacket temperature T<65° C. until volume of the residuereaches 5.4 liters (2.16 volumes). Then atmospheric pressure is built-upand jacket temperature 40-50° C. is adjusted.

The batch is stirred for not less than 10 minutes and then seeded withLaquinimod Na crystals to initiate crystallization.

The batch is stirred at 45° C. for additional 90 minutes and 7.9 volumesof acetone are added to the reactor in 1.5-2.5 hrs. Reactor temperatureduring the addition maintained between 40 and 50° C.

Resulting slurry is cooled to 0±4° C. during 3.5-4.5 hrs and stirred atthis temperature for 10-15 hrs. Then the slurry is transferred tofilter-dryer and solid is filtered under pressure of nitrogen.

The cake is washed twice (2·2 kg) with acetone, purged with nitrogen andthen dried under vacuum (P<50 mmHg) and elevated temperature (T=40° C.)at agitation.

Dry product is discharged, sampled for analysis and packed.

Discussion of Example 1:

The pilot scale process of recrystallization of laquinimod sodium wasbased on Example 15 of U.S. Pat. No. 7,884,208. The starting materialwas crude laquinimod sodium, having low particle size (d(0.1)=1.2μ,d(0.5)=6-11μ; d(0.9)=20-35μ; and appears as aggregated solid. Example 15of U.S. Pat. No. 7,884,208 involves 25.0 g of laquinimod sodium(laboratory scale) prepared according to the method disclosed in U.S.Pat. No. 6,875,869. In Example 15, the 25.0 g of laquinimod sodium isdissolved in an aqueous solution of laquinimod sodium and thenevaporated under vacuum at stirring to a concentrated solution having avolume ratio of 2.14 v/w, the resulting residue is seeded to inducecrystallization then treated with an anti-solvent (acetone).

The modified pilot scale process was performed with 2.5 kg of laquinimodsodium which is a 100-fold scale up from Example 15. In addition, themodified pilot scale process had significant differences from thelaboratory scale process of Example 15 of U.S. Pat. No. 7,884,208.Specifically, evaporation on the laboratory scale was performed in around-bottom flask in a rotary evaporator without stirring, whileevaporation on the pilot scale was performed in a reactor with stirring.On the pilot scale, the evaporation residue is stirred aggressively,liquid splashes on the reactor wails, solid depositions form, andcrystallization was spontaneous. On the laboratory scale, a metastablesolution could be concentrated to a volume ratio of 2.1-2.2 v/w at whichpoint crystallization did not take place and nucleation was controlledby seeding. On the pilot scale, conditions and concentration were suchthat spontaneous crystallization took place, i.e., crystallization wasinduced without seeding.

Surprisingly, the pilot batches did not result in laquinimod sodiumparticles having a particle site distribution expected based on Example15 of U.S. Pat. No. 7,884,208. Instead, applicants unexpected found thatthe pilot batches resulted in a mixture of recrystallized laquinimodsodium particles wherein (i) 90% or more of the total amount by volumeof the laquinimod sodium particles have a size of less than 40 microns,(ii) 50% or more of the total amount by volume of the laquinimod sodiumparticles have a size of less than 15 microns, and (iii) 10% or more ofthe total amount by volume of the laquinimod sodium particles have asize of less than 5 microns. A comparison of particle size distributionsresulting from the two different processes is shown in Table 5.

TABLE 5 Laboratory Scale Modified Pilot Scale 25 g batch 2.5 kg batchPSD by Example 15 from Pilot Scale Pilot Scale Malvern U.S. Pat. No.7,884,208 Batch A Batch B d(0.1) um 6.1 3.3 4.1 d(0.5) um 21.2 12.9 13.5D(0.9) um 51.8 33.8 33.9 Appearance White free- White free- White free-flowing powder flowing flowing powder powder

The process of U.S. Pat. No. 7,884,208 and the process of Example 1,above, each produce different products and are not equivalent processes.Applicants' pilot scale version of the process of U.S. Pat. No.7,884,208 resulted in substantially different conditions from the priorart and resulted in a substantially different product having smallerparticle sizes as shown in Table 5.

Since laquinimod Na is a potent drug substance, small particle size isadvantageous for this API. Formation of non-aggregated laquinimod sodiumcrystals with reduced particle size could provide better uniformity ofdrug product and avoid milling or de-lumping operations. The startingmaterial, crude laquinimod sodium, appears as aggregated solid. There-crystallized product is free flowing powder. Powders with smallerparticles have a stronger trend to aggregate. Crude laquinimod sodiumprepared by slurry-to-slurry recrystallization (i.e., the process ofU.S. Pat. No. 6,077,851) produces particles having a low particle sizeand are highly aggregated. The modified process produces particleshaving a low particle size and are free flowing.

The aim was scalable crystallization procedure giving smaller crystalsize, PSD and low aggregation on laboratory, pilot and commercial scale.The desirable PSD profile was the following: d(0.1)<5 μm, d(0.5)<15 μmand d(0.9)<40 μm. The method is based on spontaneous crystallizationinitiated in aqueous phase prior to acetone addition. The importantfactor affecting crystallization is initial concentration ofcrystallizing solution. In the new crystallization procedure, reducedwater volume ratio in the end of evaporation from 2.14 v/w to 1.7-1.8v/w. Higher concentration of the solution ensures initiation ofspontaneous crystallization in the end of evaporation operation andprovides higher supersaturation level and lower crystal size.

EXAMPLE 2 Recrystallization of Laquinimod Sodium—Laboratory Scale(Laboratory Scale Batch A)

All operations of Laquinimod Na re-crystallization step includingevaporation were performed on laboratory scale in transparent agitatedglass reactors equipped with stirrer, thermometers and circulating bathfor heating and cooling.

25 g crude Na Laquinimod and 275 ml deionized water introduced into 250ml stirred jacketed glass reactor. The mixture is stirred and heated to70° C., after complete dissolution of the solid the solution is filteredthrough paper filter. Resulting clear filtrate introduced to 250 mljacketed glass reactor equipped with circulating bath, stirrer,thermometer and vacuum distillation system.

Vacuum is applied and water is distilled at stirring, pressure duringthe evaporation is 38-40 mbar and jacket temperature is 55° C.

After distillation of ca. ⅔ volume spontaneous crystallization on thereactor wall above liquid level is observed.

The distillation is continued until the residue volume reaches 45 mlthen atmospheric pressure is build up and the batch is stirred at 50° C.for one hour. On this step intensive crystallization takes place.

200 ml acetone is added to the resulting slurry in one hour and thebatch is stirred for one additional hour at 50° C.

The batch is cooled to 0-5° C. during one hour and filtered on Büchnerfilter. The solid cake is washed with 75 ml of acetone.

Collected wet product (28.0 g) is dried in oven under vacuum at 50° C.to constant weight.

-   Dry product—23.8 g-   Crystallization yield—95.2%

Analysis:

Microscopic observation—rod-shape particles

-   Particle Size Distribution by Malvern:-   D(0.1)=2.3 μm-   D(0.5)=10.8 μm-   D(0.9)=32.7 μm

EXAMPLE 3 Recrystallization of Laquinimod Sodium—Laboratory Scale(Laboratory Scale Batch B)

All operations of Laquinimod Na re-crystallization step includingevaporation were performed on laboratory scale in transparent agitatedglass reactors equipped with stirrer, thermometers and circulating bathfor heating and cooling.

25 g Na laquinimod crude and 275 ml deionized water introduced into 250ml stirred jacketed glass reactor. The mixture is stirred and heated to70° C., after complete dissolution of the solid the solution is filteredthrough paper filter. Resulting clear filtrate introduced to 250 mljacketed glass reactor equipped with circulating bath, stirrer,thermometer and vacuum distillation system. Vacuum is applied and wateris distilled at stirring, pressure during the evaporation is 38-40 mbarand jacket temperature is 55° C. During the distillation spontaneouscrystallization on the reactor wall is observed when the residue volumereached ca. 120 ml. The distillation is continued until the residuevolume reaches 45 ml then atmospheric pressure is build up and the batchis stirred at 50° C. for one hour. On this step intensivecrystallization takes place.

200 ml acetone is added to the resulting slurry in one hour and thebatch is stirred for one additional hour at 50° C.

The batch is cooled to 0-5° C. during one hour, stirred at thistemperature for one additional hour and filtered on Büchner filter. Thesolid cake is washed with 75 ml of acetone.

Collected wet product (27.5 g) is dried in oven under vacuum at 50° C.to constant weight.

-   Dry product—23.65 g-   Crystallization yield—94.6%

Analysis:

-   Microscopic observation—rod-shape particles-   Particle Size Distribution by Malvern:-   D(0.1)=2.6 μm-   D(0.5)=12.4 μm-   D(0.9)=34.3 μm

TABLE 6 Laboratory scale Laquinimod Na crystallization resultsLaboratory Scale Batch No. Laboratory Laboratory Scale Scale Batch ABatch B Starting material, crude   25 g   25 g Laquinimod Na, g Dryproduct, g 23.8 g 23.65 g Crystallization yield, % 95.2% 94.6% PSDD(0.1) μm 2.3 2.6 D(0.5) μm 10.8 12.4 D(0.9) μm 32.7 34.3

Discussion of Examples 2 and 3

The results of Examples 2 and 3 are summarized in Table 6. Table 6 showsthat the process reliably produces a mixture of laquinimod sodiumcrystals a mixture of recrystallized laquinimod sodium particles wherein(i) 90% or more of the total amount by volume of the laquinimod sodiumparticles have a size of less than 40 microns, (ii) 50% or more of thetotal amount by volume of the laquinimod sodium particles have a size ofless than 15 microns, and (iii) 10% or more of the total amount byvolume of the laquinimod sodium particles have a size of less than 5microns.

EXAMPLE 4 Recrystallization of Laquinimod Sodium—Production Scale(Production Scale Batches C, D and E)

Re-crystallization of Laquinimod Na on the production scale is performedin two 250 liter glass-lined reactors (Reactor I and Reactor II). Solidproduct is filtered and dried in Hastelloy C-22 agitated filter-dryerwith 20 micron mesh.

Batch size is 6.5-7.5 kg of dry API.

Batch of crude Laquinimod Na is introduced to Reactor I with 11 volumesof process water. The batch is heated to 60-73° C. at stirring untilcomplete dissolution of solid.

The hot solution in Reactor I is circulated through 0.2 μm filtrationsystem at heating and stirring during 15-20 minutes. After thecirculation completion filtered solution is transferred to Reactor IIthrough 0.2 μm filter. Reactor I and filters washed with 1.75 volumes ofprocess water and the wash is transferred to the Reactor II.

Vacuum is build-up and the solution in the Reactor II is evaporated atP<45 mmHg and jacket temperature T<65° C. until volume of the residuereaches 14-16 liter (ca. 1.7-1.8 v/w water/weight crude laquinimod Nastarting material). On this step spontaneous crystallization isinitiated on the reactor walls. Than atmospheric pressure is build-upand jacket temperature 40-50° C. is adjusted. The batch is stirred fornot less than 10 minutes.

The batch is stirred at 45° C. for additional 90 minutes and 7.9 volumesof acetone are added to the reactor in 1.5-2.5 hrs. Reactor temperatureduring the addition maintained between 40 and 50° C.

Resulting slurry is cooled to 0±4° C. during 2-5 hrs and stirred at thistemperature for 10-15 hrs. Then the slurry is transferred tofilter-dryer and solid is filtered under pressure of nitrogen.

The cake is washed twice (2×10 liter) with acetone, purged with nitrogenand then dried under vacuum (P>50 mmHg) and elevated temperature(T=35±5° C.) at agitation.

Dry product is discharged, sampled for analysis and packed.

Data for 3 typical production GMP batches is summarized in Table 7. ThePSD values presented in Table 7 are in a good accordance to the resultsof laboratory scale experiments presented in Examples 2 and 3.

TABLE 7 Production scale Laquinimod Na crystallization resultsProduction Scale Batch No. Batch C Batch D Batch E Starting material,crude 8.50 8.55 9.45 Laquinimod Na, kg Dry product, kg 7.40 7.00 6.80Crystallization yield, % 87 82 72 Product Appercance White White Whitefree- free- free- flowing flowing flowing powder powder powder BulkDensity, g/ml 0.308 0.288 0.245 Tapped Density, g/ml 0.609 0.609 0.460PSD D(0.1) μm 4.1 4.1 2.5 D(0.5) μm 14.0 14.7 9.5 D(0.9) μm 32.0 33.621.0

Batch C and D also have reduced levels of impurities (Table 8) and goodbulk and tapped density (Table 7).

Analysis of powder density of laquinimod sodium produced on theproduction scale (22 crystallization batches) shows that the bulkdensity varies in range between 0.237 and 0.364 g/ml. Tapped density iswith 0.432 and 0.609 g/ml.

The results of analyzing Batches C and D are shown in Tables 8 and 9.

TABLE 8 Analytical Results Test Specifications Batch C Batch D Assay98.0-102.0% 99.3% 99.9% (by HPLC) Related Polar MCQ NMT 0.15% LT 0.02%LT 0.02% Substances MCQCA NMT 0.15% LT 0.03% LT 0.03% (by HPLC) MCQEENMT 0.10% LT 0.02% LT 0.02% MCQME NMT 0.12% LT 0.02% LT 0.02% 5-HLAQ NMT0.10% LT 0.02% LT 0.02% Any other NMT 0.10% LT 0.02% LT 0.02% impuritiesTotal NMT 1.00% LT 0.05% LT 0.05% impurities Related N-Ethyl NMT 0.10%LT 0.02% LT 0.02% Non-polar aniline Substances Any other NMT 0.10% LT0.02% LT 0.02% (by HPLC) impurities Total NMT 0.50% LT 0.02% LT 0.02%impurities Des-ethyl NMT 0.10% LT 0.1% LT 0.1% laquinimod (DELAQ)content (by HPLC) LAQ content by NMT 1.00% LT 0.2% LT 0.2% HPLC)Dimethylmalonate NMT 0.10% LT 0.05% LT 0.05% content (by HPLC) DimethylNMT 1 ppm LT 1 ppm LT 1 ppm sulfate content (by LC-MS) Water (by K.F NMT1.5% (w/w 0.3% 0.2% coulometric) (w/w) (w/w) Heavy metals NMT 0.02% ppmLT 20 ppm LT 20 ppm (by IPC-AES) Sodium content 5.8-6.4%  6.1%  6.1%Residual Ethanol NMT 5000 ppm LT 5 ppm LT 5 ppm solvents n-Heptane NMT5000 ppm LT 10 ppm LT 10 ppm n-octane NMT 2000 ppm LT 10 ppm LT 10 ppmMethanol NMT 3000 ppm LT 30 ppm LT 30 ppm Acetone NMT 5000 ppm LT 250ppm LT 250 ppm Dioxance NMT 380 ppm LT 10 ppm LT 10 ppm DMF NMT 880 ppmLT 40 ppm LT 40 ppm Microbiological Total NMT 1000 CFU/g LT LT testsviable 10 CFU/g 10 CFU/g aerobic count Fungi/ NMT 100 CFU/g LT LT yeasts10 CFU/g 10 CFU/g and moulds Escherica Absence of Absence Absence ColiE-Coli

TABLE 9 Metal impurities in PPM of Laquinimod Sodium Example 1, (BatchExample D) of 17 of U.S. U.S. Example 4 Example 4 Pat. No. Pat. No. NewNew Impurity 7,884,208 7,884,208 Batch C Batch D Al 14.0 5.6 1.63 1.13Ca 165 65 6.3 22 Cr 2.6 <0.5 0.55 <0.26 Cu 2.8 1.3 0.325 <0.26 Fe 31.55.8 3.44 3.55 Ni 5.5 <0.5 0.79 0.61 S 466 <1 6.7 3.9 Zn 20.5 7.5 <1 3.15

TABLE 10 Purification of Laquinimod Sodium from MCQME Starting material,Re-crystallized Crude product Batch No. Crude C Appearance Aggregatedwhite Free-flowing white solid powder MCQME by HPLC, % 0.10 N.D.**N.D.—Not Detected (<0.02%)

Microscopic photographs of typical batches of Crude and re-crystallizedLaquinimod Na at different magnification are presented in FIGS. 1-4.

Discussion of Example 4:

The modified crystallization procedure demonstrates good reproducibilityof particle size distribution on the production scale. Reduction of theevaporation residue volume to a ratio of 1.7-1.8 v/w and initiation ofspontaneous crystallization provided desirable crystal size. Improvedcrystallization procedure demonstrates reduction in crystal size to alevel of d(0.9)<40 μm and good reproducibility of Particle SizeDistribution on the production scale.

The product with reduced crystal size has no trend to aggregation anddoes not need milling or de-lumping for homogenization. The product withsimilar PSD prepared by slurry-to-slurry procedure is aggregated andthus problematic in formulation.

The modified crystallization procedure also results in laquinimod sodiumhaving desirable density and purity profiles.

The improved crystallization procedure also provides effectivepurification from organic impurities, e.g., MCQME.

The data shown in Table 10 demonstrates complete removal of MCQMEimpurity by re-crystallization of commercial scale batch of Laquinimodsodium. Since this intermediate has genotoxic potential it should bepurified to undetectable level. The crystallization process providesalso purification of all other known organic impurities to the levelbelow the limit of detection.

Microscopic photographs of typical batches of crude and re-crystallizedLaquinimod sodium at different magnification are presented on FIGS. 5-8and show rod-shape morphology of the both products. At the same time,the Crude presented on FIGS. 5 and 6 are much more aggregated than there-crystallized “Cryst” product of FIGS. 7 and 8.

EXAMPLE 5 Laquinimod Capsules of Pharmaceutical Composition ofLaquinimod Sodium

Laquinimod capsules are manufactured according to the method asdescribed in Example 2 of PCT International Application publication No.WO 2007/146248, the entire content of which is hereby incorporated byreference. Steps of Example 2 of WO 2007/146248 are performed. Eachcapsule contains 0.64 mg of laquinimod sodium equivalent to 0.6 mglaquinimod.

The capsule has quantities of impurities below the following limitsbased on HPLC relative to the amount of laquinimod.

TABLE 11 Impurities in Laquinimod Capsules Impurity Amount Sum of MCQMCQCA NMT 0.5% 5-HLAQ NMT 0.5% Any Other Polar Impurity/Degradation NMT0.5% Product Total Polar Impurities NMT 2.0% N-Ethylaniline NMT 0.5%3-HLAQ NMT 0.5% Any Other Non-Polar NMT 0.5% Impurity/DegradationProduct Total Non-polar Impurities NMT 1.0% MEG-LAQ NMT 1.0%

The capsules have a water content of no more than 1.5%.

The dissolution profiles, content uniformity, and residual solvents ofthe encapsulated pharmaceutical composition conforms to U.S.Pharmacopeia <711> (dissolution), U.S. Pharmacopeia <905> (uniformity),and U.S. Pharmacopeia <467>.

Each capsule contains 90.0-110.0% of the labeled amount.

The capsules contain a total aerobic microbial count (TAMC) of NMT 10³cfu/g, a total combined yeasts/moulds count (TYMC) of NMT 10² cfu/g, andan absence of Escherichia Coli in 1 g.

Discussion of Example 5:

Example 5 demonstrates that, in a commercial-scale production,pharmaceutical compositions of laquinimod can be prepared withnon-detectable levels or a low level of polar impurities and non-polarimpurities.

REFERENCES

-   1. U.S. Pat. No. 6,077,851;-   2. U.S. Pat. No. 6,875,869;-   3. U.S. Pat. No. 7,589,208;-   4. U.S. Pat. No. 7,884,208;-   5. U.S. Pat. No. 7,989,473;-   6. U.S. Pat. No. 8,178,127;-   7. U.S. Patent Application Publication No. 2006/0188581 A1;-   8. PCT International Application Publication No. WO 2005/074899;-   9. 21 C.F.R. §211.166;-   10. Felmeister, A. Chpt 88, Remington's Pharmaceutical Sciences,    15^(th) Edition, Mack Publishing Company, Easton, Pa. (1975);-   11. Hausner, “The Role of Particle Size in the Development of    Genetic Products” 2003;-   12. Brumfitt, W. and J. M. T. Hamilton-Miller, J. Antimicrobial    Chemotherapy 42:363:371 (1998);-   13. Rudnic et al. Chpt. 45, Remington's Pharmaceutical Sciences,    20^(th) Edition, Lippincott Williams & Wilkins, Baltimore, Md.    (2000);-   14. United States Pharmacopeia XXV (2000);-   15. United States Pharmacopeia 34/National Formulary 23, (2011);-   16. 7 Modern Pharmaceutics, Chapters 3 and 10 (Banker & Rhodes,    editors, 1979);-   17. Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981);-   18. Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition    (1976);-   19. Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing    Company, Easton, Pa., 1985);-   20. Advances in Pharmaceutical Sciences (David Ganderton, Trevor    Jones, Eds., 1992);-   21. Advances in Pharmaceutical Sciences Vol. 7, (David Ganderton,    Trevor Jones, James McGinity, Eds., 1995);-   22. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms    (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity,    Ed., 1989);-   23. Pharmaceutical Particulate Carriers: Therapeutic Applications:    Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed.,    1993);-   24. Drug Delivery to the Gastrointestinal Tract. (Ellis Horwood    Books in the Biological Sciences, Series in Pharmaceutical    Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.) (1989);-   25. Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol    40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.) (1996); and-   26. Vogel'Textbook of Practical Organic Chemistry, 5^(th) edition.    Longman Scientific & Technical, 1989.

1. A mixture of crystalline laquinimod sodium particles, wherein (i) 90%or more of the total amount by volume of the laquinimod sodium particleshave a size of 40 microns or less and (ii) 50% or more of the totalamount by volume of the laquinimod sodium particles have a size of 15microns or less, and wherein: a) the mixture has a bulk density of 0.2g/mL to 0.4 g/mL; b) the mixture has a tapped density of 0.40 g/mL to0.7 g/mL; c) an amount of heavy metal in the mixture is no more than0.002% of heavy metal relative to the amount by weight of laquinimodsodium; d) an amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in themixture is no more than 0.15% relative to the amount of laquinimodsodium as measured by HPLC; e) an amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(MCQCA) in the mixture is no more than 0.15% relative to the amount oflaquinimod sodium as measured by HPLC; or f) an amount of methyl5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate(MCQME) in the mixture is no more than 0.12% relative to the amount oflaquinimod sodium as measured by HPLC.
 2. (canceled)
 3. The mixture ofclaim 1, wherein 10% or more of the total amount by volume of thelaquinimod sodium particles have a size of 5 microns or less andwherein: a) the mixture has a tapped density of 0.40 g/mL to 0.7 g/mL;or b) an amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in themixture is no more than 0.15% relative to the amount of laquinimodsodium as measured by HPLC.
 4. The mixture of claim 1, wherein (i) 90%or more of the total amount by volume of the laquinimod sodium particleshave a size of less than 40 microns, (ii) 50% or more of the totalamount by volume of the laquinimod sodium particles have a size of lessthan 15 microns, and (iii) 10% or more of the total amount by volume ofthe laquinimod sodium particles have a size of less than 5 microns andwherein: a) the mixture has a bulk density of 0.2 g/mL to 0.4 g/mL; b)the mixture has a tapped density of 0.40 g/mL to 0.7 g/mL; c) an amountof heavy metal in the mixture is no more than 0.002% of heavy metalrelative to the amount by weight of laquinimod sodium; d) an amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in themixture is no more than 0.15% relative to the amount of laquinimodsodium as measured by HPLC; e) an amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(MCQCA) in the mixture is no more than 0.15% relative to the amount oflaquinimod sodium as measured by HPLC; or f) an amount of methyl5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate(MCQME) in the mixture is no more than 0.12% relative to the amount oflaquinimod sodium as measured by HPLC.
 5. The mixture of claim 1wherein: a) the mixture is prepared in a single batch comprising 2.5 kgor more of laquinimod sodium, b) the size and amount by volume oflaquinimod sodium particles are determined based on an unmilled sampleof the mixture, c) the size and amount by volume of laquinimod sodiumparticles are determined based on a milled sample of the mixture, d) anamount of aluminum in the mixture is less than 5 ppm relative to theamount by weight of laquinimod sodium, e) an amount of calcium in themixture is less than 60 ppm relative to the amount by weight oflaquinimod sodium, f) an amount of copper in the mixture is less than 1ppm relative to the amount by weight of laquinimod sodium, g) an amountof iron in the mixture is less than 4 ppm relative to the amount byweight of laquinimod sodium, and/or h) an amount of zinc in the mixtureis less than 7 ppm relative to the amount by weight of laquinimodsodium. 6-21. (canceled)
 22. The mixture of claim 1, wherein: a) a totalamount of polar impurities in the mixture is no more than 1.00% relativeto the amount of laquinimod sodium as measured by HPLC, b) an amount ofethyl5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate(MCQEE) in the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC, c) a total amount of non-polarimpurities in the mixture is no more than 0.50% relative to the amountof laquinimod sodium as measured by HPLC, d) an amount of N-ethylaniline in the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC, e) an amount ofN-ethyl-4,5-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydroquinoline-3-carboxamide(5-HLAQ) in the mixture is no more than 0.10% relative to the amount orlaquinimod sodium as measured by HPLC, f) an amount of5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide(DELAQ) in the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC, g) an amount of laquinimod acidin the mixture is no more than 1.00% relative to the amount oillaquinimod sodium as measured by HPLC, h) an amount of dimethyl malonatein the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC, i) an amount of diethyl malonatein the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC, j) an amount of dimethyl sulfatein the mixture is no more than 1 ppm relative to the amount by weight oflaquinimod sodium, k) an amount of water in the mixture is no more than1.5% by weight relative to the amount of laquinimod sodium as measuredby K.F. coulometric titration, l) an amount of sodium from 5.8% to 6.4%relative to the amount by weight of laquinimod sodium, m) an amount ofethanol in the mixture is no more than 5000 ppm relative to the amountby weight of laquinimod sodium, n) an amount of n-heptane in the mixtureis no more than 5000 ppm relative to the amount by weight of laquinimodsodium, o) an amount of n-octane in the mixture is no more than 2000 ppmrelative to the amount by weight of laquinimod sodium, p) an amount ofmethanol in the mixture is no more than 3000 ppm relative to the amountby weight of laquinimod sodium, q) an amount of acetone in the mixtureis no more than 5000 ppm relative to the amount by weight of laquinimodsodium, r) an amount of dioxane in the mixture is no more than 380 ppmrelative to the amount by weight of laquinimod sodium, or s) an amountof dimethyl formamide in the mixture is no more than 880 ppm relative tothe amount by weight of laquinimod sodium.
 23. The mixture of claim 1,wherein: a) an amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in themixture is no more than 0.15% relative to the amount of laquinimodsodium as measured by HPLC, b) an amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(MCQCA) in the mixture is no more than 0.15% relative to the amount oflaquinimod sodium as measured by HPLC; or c) an amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate(MCQME) in the mixture is no more than 0.12% relative to the amount oflaquinimod sodium as measured by HPLC, d) the mixture has a bulk densityof 0.2 g/mL to 0.4 g/mL, e) the mixture has a tapped density of 0.40g/mL to 0.7 g/mL, f) an amount of heavy metal in the mixture is no morethan 0.002% of heavy metal relative to the amount by weight oflaquinimod sodium, g) a total amount of polar impurities in the mixtureis no more than 1.00% relative to the amount of laquinimod sodium asmeasured by HPLC, h) an amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate(MCQEE) in the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC, i) a total amount of non-polarimpurities in the mixture is no more than 0.50% relative to the amountof laquinimod sodium as measured by HPLC, j) an amount of N-ethylaniline in the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC, k) an amount ofN-ethyl-4,5-dihydroxy-1-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydroquinoline-3-carboxamide(5-HLAQ) in the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC, l) an amount of5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide(DELAQ) in the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC, m) an amount of laquinimod acidin the mixture is no more than 1.00% relative to the amount oflaquinimod sodium as measured by HPLC, n) an amount of dimethyl malonatein the mixture is no more than 0-10% relative to the amount oflaquinimod sodium as measured by HPLC, o) an amount of diethyl malonatein the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC, p) an amount of dimethyl sulfatein the mixture is no more than 1 ppm relative to the amount by weight oflaquinimod sodium, q) an amount of water in the mixture is no more than1.5% by weight relative to the amount of laquinimod sodium as measuredby K.F. coulometric titration, r) an amount of sodium from 5.8% to 6.4%relative to the amount by weight of laquinimod sodium s) an amount ofethanol in the mixture is no more than 5000 ppm relative to the amountby weight of laquinimod sodium, t) an amount of n-heptane in the mixtureis no more than 5000 ppm relative to the amount by weight of laquinimodsodium, u) an amount of n-octane in the mixture is no more than 2000 ppmrelative to the amount by weight of laquinimod sodium, v) an amount ofmethanol in the mixture is no more than 3000 ppm relative to the amountby weight of laquinimod sodium, w) an amount of acetone in the mixtureis no more than 5000 ppm relative to the amount by weight of laquinimodsodium, x) an amount of dioxane in the mixture is no more than 380 ppmrelative to the amount by weight of laquinimod sodium, and y) an amountof dimethyl formamide in the mixture is no more than 880 ppm relative tothe amount by weight of laquinimod sodium. 24-43. (canceled)
 44. Apharmaceutical composition comprising the mixture of claim 1 and apharmaceutically acceptable carrier.
 45. The pharmaceutical compositionof claim 44, wherein: a) a total amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) and5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(MCQCA) in the pharmaceutical composition is no more than 0.50% relativeto the amount of laquinimod sodium as measured by HPLC, b) a totalamount of polar impurities in the pharmaceutical composition is no morethan 2.00% relative to the amount of laquinimod sodium as measured byHPLC, c) an amount of N-ethyl aniline in the pharmaceutical compositionis no more than 0.50% relative to the amount of laquinimod sodium asmeasured by HPLC, d) an amount5-chloro-N-ethyl-3-hydroxy-1-methyl-5-2,4-dioxo-N-phenyl-1,2,3,4-tetrahydroquinoline-3-carboxamide(3-HLAQ) in the pharmaceutical composition is no more than 0.50%relative to the amount of laquinimod sodium as measured by HPLC, e) atotal amount of non-polar impurities in the pharmaceutical compositionis no more than 1.00% relative to the amount of laquinimod sodium asmeasured by HPLC, f) an amount ofN-ethyl-4-hydroxy-1-methyl-5-(methyl(2,3,4,5,6-pentahydroxyhexyl)amino)-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide(MEG-LAQ) in the pharmaceutical composition is no more than 1.00%relative to the amount of laquinimod sodium as measured by HPLC, g) anamount of water in the pharmaceutical composition is no more than 1.50%relative to the amount of laquinimod sodium as measured by K.F.coulometric titration, h) an amount of water in the pharmaceuticalcomposition is no more than 0.80% relative to the amount of laquinimodsodium as measured by K.F. coulometric titration, i) an amount ofethanol in the pharmaceutical composition is no more than 5000 ppmrelative to the amount by weight of laquinimod sodium, j) an amount ofn-heptane in the pharmaceutical composition is no more than 5000 ppmrelative to the amount by weight of laquinimod sodium, k) an amount ofn-octane in the pharmaceutical composition is no more than 2000 ppmrelative to the amount by weight of laquinimod sodium, l) an amount ofmethanol in the pharmaceutical composition is no more than 3000 ppmrelative to the amount by weight of laquinimod sodium, m) an amount ofacetone in the pharmaceutical composition is no more than 5000 ppmrelative to the amount by weight of laquinimod sodium, n) an amount ofdioxane in the pharmaceutical composition is no more than 380 ppmrelative to the amount by weight of laquinimod sodium, o) an amount ofdimethyl formamide in the pharmaceutical composition is no more than 880ppm relative to the amount by weight of laquinimod sodium, or p) anamount of sodium in the pharmaceutical composition is from 5.8% to 6.4%relative to the amount by weight of laquinimod sodium.
 46. Thepharmaceutical composition of claim 44, wherein: a) a total amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) and5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(MCQCA) in the pharmaceutical composition is no more than 0.50% relativeto the amount of laquinimod sodium as measured by HPLC, b) a totalamount of polar impurities in the pharmaceutical composition is no morethan 2.00% relative to the amount of laquinimod sodium as measured byHPLC, c) an amount of N-ethyl aniline in the pharmaceutical compositionis no more than 0.50% relative to the amount of laquinimod sodium asmeasured by HPLC, d) an amount5-chloro-N-ethyl-3-hydroxy-1-methyl-5-2,4-dioxo-N-phenyl-1,2,3,4-tetrahydroquinoline-3-carboxamide(3-HLAQ) in the pharmaceutical composition is no more than 0.50%relative to the amount of laquinimod sodium as measured by HPLC, e) atotal amount of non-polar impurities in the pharmaceutical compositionis no more than 1.00% relative to the amount of laquinimod sodium asmeasured by HPLC, f) an amount ofN-ethyl-4-hydroxy-1-methyl-5-(methyl(2,3,4,5,6-pentahydroxyhexyl)amino)-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide(MEG-LAQ) in the pharmaceutical composition is no more than 1.00%relative to the amount of laquinimod sodium as measured by HPLC, g) anamount of water in the pharmaceutical composition is no more than 1.50%or no more than 0.80% relative to the amount of laquinimod sodium asmeasured by K.F. coulometric titration, h ) an amount of ethanol in thepharmaceutical composition is no more than 5000 ppm relative to theamount by weight of laquinimod sodium, i) an amount of n-heptane in thepharmaceutical composition is no more than 5000 ppm relative to theamount by weight of laquinimod sodium, j) an amount of n-octane in thepharmaceutical composition is no more than 2000 ppm relative to theamount by weight of laquinimod sodium, k) an amount of methanol in thepharmaceutical composition is no more than 3000 ppm relative to theamount by weight of laquinimod sodium, l) an amount of acetone in thepharmaceutical composition is no more than 5000 ppm relative to theamount by weight of laquinimod sodium, m) an amount of dioxane in thepharmaceutical composition is no more than 380 ppm relative to theamount by weight of laquinimod sodium, and n) an amount of dimethylformamide in the pharmaceutical composition is no more than 880 ppmrelative to the amount by weight of laquinimod sodium. 47-60. (canceled)61. A method of treating a subject afflicted with or for alleviating asymptom of a form of multiple sclerosis, lupus nephritis, lupusarthritis, rheumatoid arthritis, a BDNF-related disorder, Crohn'sdisease, a GABA-related disorder, a cannabinoid receptor type 1 (CB1)mediated disorder, or an ocular inflammatory disorder comprisingadministering to the subject the pharmaceutical composition of claim 44so as to thereby treat or alleviate the symptom of multiple sclerosis inthe subject. 62-64. (canceled)
 65. A process of recrystallization oflaquinimod sodium comprising: a) dissolving an amount of laquinimodsodium in water to form an aqueous solution; b) concentrating theaqueous solution to form a concentrated solution comprisingapproximately 1.7-1.8 mL of water per gram of laquinimod sodium; c)adding acetone to the concentrated solution of step b); and d) isolatingrecrystallized laquinimod sodium.
 56. The process of claim 65, wherein:a) the amount of laquinimod sodium in step a) is 2.5 kg or greater, b)step a) is performed with 10-12 mL of water per gram of laquinimodsodium, c) step a) is performed by heating the aqueous solution to atemperature of 58-75° C., d) crystallization occurs after step a) andbefore step c), e) crystallization is induced by rapid stirring duringor after the concentrating step b) or by addition of a seed crystalduring or after the concentrating step b), f) crystallization occurswithout addition of a seed crystal, g) step b) is performed underconditions appropriate to induce crystallization at the concentration of1.7-1.8 mL of water per gram of laquinimod sodium, h) step b) isperformed at 28-45° C., i) step c) is performed with the concentratedsolution at 40-55° C., j) step c) is performed with 6-12 mL of acetoneper gram of laquinimod sodium, k) step c) is performed over a period of1-4 hours, l) step c) is followed by cooling the solution to atemperature no less than −14° C. and no more than 6° C., m) step d)further comprises washing the recrystallized laquinimod sodium with 1-4mL of acetone per gram of crude laquinimod sodium used in step a),and/or n) step d) further comprises drying the recrystallized laquinimodsodium for no less than one hour at 30-40° C. under a vacuum of no morethan 50 mmHg. 67-90. (canceled)
 91. The process of claim 65, wherein theisolated recrystallized laquinimod sodium in step d) is a mixture ofcrystalline laquinimod sodium particles having a particle sizedistribution such that (i) 90% or more of the total amount by volume ofthe laquinimod sodium particles have a size of 40 microns or less, (ii)50% or more of the total amount by volume of the laquinimod sodiumparticles have a size of 15 microns or less, and (iii) 10% or more ofthe total amount by volume of the laquinimod sodium particles have asize of less than 5 microns or less.
 92. A mixture of crystallinelaquinimod sodium particles prepared by claim
 65. 93. The mixture ofclaim 92, wherein (i) 90% or more of the total amount by volume of thelaquinimod sodium particles have a size of 40 microns or less, (ii) 50%or more of the total amount by volume of the laquinimod sodium particleshave a size of 15 microns or less, and (iii) 10% or more of the totalamount by volume of the laquinimod sodium particles have a size of 5microns or less.
 94. The mixture of claim 92, wherein: a) the mixturehas a bulk density of 0.2 g/mL to 0.4 g/mL; b) the mixture has a tappeddensity of 0.40 g/mL to 0.7 g/mL; c) an amount of aluminium in themixture is less than 5 ppm relative to the amount by weight oflaquinimod sodium; d) an amount of calcium in the mixture is less than60 ppm relative to the amount by weight of laquinimod sodium; e) anamount of copper in the mixture is less than 1 ppm relative to theamount by weight of laquinimod sodium; f) an amount of iron in themixture is less than 4 ppm relative to the amount by weight oflaquinimod sodium; g) an amount of zinc in the mixture is less than 7ppm relative to the amount by weight of laquinimod sodium; h) an amountof heavy metal in the mixture is no more than 0.002% relative to theamount by weight of laquinimod sodium; i) a total amount of polarimpurities in the mixture is no more than 1.00% relative to the amountof laquinimod sodium as measured by HPLC; j) an amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in themixture is no more than 0.15% relative to the amount of laquinimodsodium as measured by HPLC; k) an amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(MCQCA) in the mixture is no more than 0.15% relative to the amount oflaquinimod sodium as measured by HPLC; l) an amount of methyl5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate(MCQME) in the mixture is no more than 0.12% relative to the amount oflaquinimod sodium as measured by HPLC; m) an amount of ethyl5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate(MCQEE) in the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC; n) a total amount of non-polarimpurities in the mixture is no more than 0.50% relative to the amountof laquinimod sodium as measured by HPLC; o) an amount of N-ethylaniline in the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC; p) an amount of laquinimod acidin the mixture is no more than 1.00% relative to the amount oflaquinimod sodium as measured by HPLC; q) an amount of dimethyl malonatein the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC; r) an amount of diethyl malonatein the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC; s) an amount of dimethyl sulfatein the mixture is no more than 1 ppm relative to the amount by weight oflaquinimod sodium; t) an amount of water in the mixture is no more than1.5% by weight relative to the amount of laquinimod sodium as measuredby K.F. coulometric titration; u) the mixture comprises an amount ofsodium from 5.8% to 6.4% relative to the amount by weight of laquinimodsodium; v) an amount of ethanol in the mixture is no more than 5000 ppmrelative to the amount by weight of laquinimod sodium; w) an amount ofn-heptane in the mixture is no more than 5000 ppm relative to the amountby weight of laquinimod sodium; x) an amount of n-heptane in the mixtureis no more than 2000 ppm n-octane relative to the amount by weight oflaquinimod sodium; y) an amount of methanol in the mixture is no morethan 3000 ppm relative to the amount by weight of laquinimod sodium; z)an amount of acetone in the mixture is no more than 5000 ppm relative tothe amount by weight of laquinimod sodium; aa) an amount of dioxane inthe mixture is no more than 380 ppm relative to the amount by weight oflaquinimod sodium; or bb) an amount of dimethyl formamide in the mixtureis no more than 880 ppm relative to the amount by weight of laquinimodsodium.
 95. The mixture of claim 92, wherein: a) the mixture has a bulkdensity of 0.2 g/mL to 0.4 g/mL; b) the mixture has a tapped density of0.40 g/mL to 0.7 g/mL; c) an amount of aluminium in the mixture is lessthan 5 ppm relative to the amount by weight of laquinimod sodium; d) anamount of calcium in the mixture is less than 60 ppm relative to theamount by weight of laquinimod sodium; e) an amount of copper in themixture is less than 1 ppm relative to the amount by weight oflaquinimod sodium; f) an amount of iron in the mixture is less than 4ppm relative to the amount by weight of laquinimod sodium; g) an amountof zinc in the mixture is less than 7 ppm relative to the amount byweight of laquinimod sodium; h) an amount of heavy metal in the mixtureis no more than 0.002% relative to the amount by weight of laquinimodsodium; i) a total amount of polar impurities in the mixture is no morethan 1.00% relative to the amount of laquinimod sodium as measured byHPLC; j) an amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) in themixture is no more than 0.15% relative to the amount of laquinimodsodium as measured by HPLC; k) an amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(MCQCA) in the mixture is no more than 0.15% relative to the amount oflaquinimod sodium as measured by HPLC; l) an amount of methyl5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate(MCQME) in the mixture is no more than 0.12% relative to the amount oflaquinimod sodium as measured by HPLC; m) an amount of ethyl5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate(MCQEE) in the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC; n) a total amount of non-polarimpurities in the mixture is no more than 0.50% relative to the amountof laquinimod sodium as measured by HPLC; o) an amount of N-ethylaniline in the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC; p) an amount of laquinimod acidin the mixture is no more than 1.00% relative to the amount oflaquinimod sodium as measured by HPLC; q) an amount of dimethyl malonatein the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC; r) an amount of diethyl malonatein the mixture is no more than 0.10% relative to the amount oflaquinimod sodium as measured by HPLC; s) an amount of dimethyl sulfatein the mixture is no more than 1 ppm relative to the amount by weight oflaquinimod sodium; t) an amount of water in the mixture is no more than1.5% by weight relative to the amount of laquinimod sodium as measuredby K.F. coulometric titration; u) the mixture comprises an amount ofsodium from 5.8% to 6.4% relative to the amount by weight of laquinimodsodium; v) an amount of ethanol in the mixture is no more than 5000 ppmrelative to the amount by weight of laquinimod sodium; w) an amount ofn-heptane in the mixture is no more than 5000 ppm relative to the amountby weight of laquinimod sodium; x) an amount of n-heptane in the mixtureis no more than 2000 ppm n-octane relative to the amount by weight oflaquinimod sodium; y) an amount of methanol in the mixture is no morethan 3000 ppm relative to the amount by weight of laquinimod sodium; z)an amount of acetone in the mixture is no more than 5000 ppm relative tothe amount by weight of laquinimod sodium; aa) an amount of dioxane inthe mixture is no more than 380 ppm relative to the amount by weight oflaquinimod sodium; and bb) an amount of dimethyl formamide in themixture is no more than 880 ppm relative to the amount by weight oflaquinimod sodium.
 95. A pharmaceutical composition comprising themixture of claim 92 and a pharmaceutically acceptable carrier.
 97. Thepharmaceutical composition of claim 96, wherein: a) a total amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) and5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(MCQCA) in the pharmaceutical composition is no more than 0.50% relativeto the amount of laquinimod sodium as measured by HPLC; b) a totalamount of polar impurities in the pharmaceutical composition is no morethan 2.00% relative to the amount of laquinimod sodium as measured byHPLC; c) an amount of N-ethyl aniline in the pharmaceutical compositionis no more than 0.50% relative to the amount of laquinimod sodium asmeasured by HPLC; d) a total amount of non-polar impurities in thepharmaceutical composition is no more than 1.00% relative to the amountof laquinimod sodium as measured by HPLC; e) an amount of water in thepharmaceutical composition is no more than 0.80% relative to the amountof laquinimod sodium as measured by K.F. coulometric titration; f) thepharmaceutical composition comprises an amount of sodium from 5.8% to6.4% relative to the amount by weight of laquinimod sodium; g) an amountof ethanol in the pharmaceutical composition is no more than 5000 ppmrelative to the amount by weight of laquinimod sodium; h) an amount ofn-heptane in the pharmaceutical composition is no more than 5000 ppmrelative to the amount by weight of laquinimod sodium; i) an amount ofn-octane in the pharmaceutical composition is no more than 2000 ppmrelative to the amount by weight of laquinimod sodium; j ) an amount ofmethanol in the pharmaceutical composition is no more than 3000 ppmrelative to the amount by weight of laquinimod sodium; k) an amount ofacetone in the pharmaceutical composition is no more than 5000 ppmrelative to the amount by weight of laquinimod sodium; l) an amount ofdioxane in the pharmaceutical composition is no more than 380 ppmrelative to the amount by weight of laquinimod sodium; or m) an amountof dimethyl formamide in the pharmaceutical composition is no more than880 ppm relative to the amount by weight of laquinimod sodium.
 98. Thepharmaceutical composition of claim 96, comprising: a) a total amount of5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline (MCQ) and5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(MCQCA) in the pharmaceutical composition is no more than 0.50% relativeto the amount of laquinimod sodium as measured by HPLC; b) a totalamount of polar impurities in the pharmaceutical composition is no morethan 2.00% relative to the amount of laquinimod sodium as measured byHPLC; c) an amount of N-ethyl aniline in the pharmaceutical compositionis no more than 0.50% relative to the amount of laquinimod sodium asmeasured by HPLC; d) a total amount of non-polar impurities in thepharmaceutical composition is no more than 1.00% relative to the amountof laquinimod sodium as measured by HPLC; e) an amount of water in thepharmaceutical composition is no more than 0.80% relative to the amountof laquinimod sodium as measured by K.F. coulometric titration; f) thepharmaceutical composition comprises an amount of sodium from 5.8% to6.4% relative to the amount by weight of laquinimod sodium; g) an amountof ethanol in the pharmaceutical composition is no more than 5000 ppmrelative to the amount by weight of laquinimod sodium; h) an amount ofn-heptane in the pharmaceutical composition is no more than 5000 ppmrelative to the amount by weight of laquinimod sodium; i) an amount ofn-octane in the pharmaceutical composition is no more than 2000 ppmrelative to the amount by weight of laquinimod sodium; j) an amount ofmethanol in the pharmaceutical composition is no more than 3000 ppmrelative to the amount by weight of laquinimod sodium; k) an amount ofacetone in the pharmaceutical composition is no more than 5000 ppmrelative to the amount by weight of laquinimod sodium; l) an amount ofdioxane in the pharmaceutical composition is no more than 380 ppmrelative to the amount by weight of laquinimod sodium; and m) an amountof dimethyl formamide in the pharmaceutical composition is no more than880 ppm relative to the amount by weight of laquinimod sodium. 99.(canceled)
 100. (canceled)